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Wilson disease: Management

Wilson disease: Management
Literature review current through: Jan 2024.
This topic last updated: Dec 08, 2023.

INTRODUCTION — Wilson disease (also referred to as hepatolenticular degeneration) is a genetic disorder of copper metabolism with an autosomal recessive pattern of inheritance that leads to impaired function of the intracellular copper transporter ATP7B. Reduced biliary excretion of copper leads to its accumulation in the liver and other tissues (eg, brain, cornea). Most patients present with liver disease that ranges from asymptomatic elevations in serum aminotransferases or bilirubin to acute liver failure or chronic hepatitis. In addition, some patients develop neuropsychiatric symptoms. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Clinical features'.)

This topic will discuss management of Wilson disease. Other aspects of Wilson disease, including screening asymptomatic relatives, are discussed separately:

Epidemiology and pathogenesis – (See "Wilson disease: Epidemiology and pathogenesis".)

Clinical manifestations and diagnosis – (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)

Interpretation of genetic testing for ATP7B (Wilson disease gene) – (See "Gene test interpretation: ATP7B (Wilson disease gene)".)

PRETREATMENT EVALUATION — Prior to initiating pharmacologic therapy, we obtain or review the following studies:

24-hour urinary copper excretion

Ceruloplasmin

International normalized ratio (INR)

Iron studies and ferritin

Serum aminotransferases – Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

Serum copper

Serum creatinine

Serum sodium

Total bilirubin

Uric acid [1]

Urinalysis

We use values for total bilirubin, INR, serum creatinine, and serum sodium to calculate the Model for End-stage Liver Disease (MELD) score. (See "Model for End-stage Liver Disease (MELD)".)

If a liver biopsy was not performed during the diagnostic evaluation, we obtain ultrasound-based transient elastography to evaluate for liver fibrosis. (See "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography" and 'Patients with cirrhosis' below.)

Baseline studies are used for assessing disease activity and monitoring response to therapy.

TREATMENT GOALS — Goals of therapy for Wilson disease include:

Removing copper that has accumulated in tissue

Preventing copper from reaccumulating in tissue

Improving symptoms (or preventing the development of symptoms)

Improving and maintaining liver synthetic function (eg, resolution of jaundice, ascites, correcting abnormalities in coagulation and in serum albumin)

INITIAL MANAGEMENT

General measures — The following measures apply to patients with Wilson disease:

Dietary modifications – During the initial phase of treatment, patients should avoid consuming food with high copper content (ie, shellfish, nuts, chocolate, mushrooms, and organ meats). However, dietary copper restriction is insufficient as sole therapy for Wilson disease.

For patients who are stable on maintenance therapy, moderate intake of copper (eg, <2 mg copper daily) may be reasonable. A detailed list of the mineral content of foods is available on the United States Department of Agriculture website.  

We advise patients who consume well water to test the water for copper content or use filters that remove trace elements. Municipal water supplies usually do not require analysis. We also advise patients who have copper pipes in the household to flush the system (ie, run the water until it is cool) before each use when using water for cooking or consumption.

Immunizations – Vaccinations for hepatitis A virus and hepatitis B virus are given to patients without serologic evidence of immunity. Additional vaccines for patients with chronic liver disease include immunizations that are given to the general population (eg, influenza). Immunization schedules are described separately. (See "Immunizations for adults with chronic liver disease".)

Abstain from alcohol We advise patients to abstain from alcohol and, in particular, to avoid heavy alcohol use (ie, >14 drinks per week or >4 drinks on a given day for males and >7 drinks per week or >3 drinks on a given day for females) [2].

Specialty referrals – We suggest that patients with Wilson disease are referred to a hepatologist for long-term management. In addition, we refer patients with neurologic symptoms (eg, tremor) to a neurologist with expertise in movement disorders. Other referrals include psychiatry for patients with psychiatric symptoms, registered dieticians for nutritional counseling, and genetic counseling for molecular genetic testing if genetic testing was not performed as part of the diagnostic evaluation. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Diagnostic evaluation'.)

Selecting initial therapy — Selecting an initial therapy is informed by whether the patient has symptoms and/or evidence of organ damage related to copper accumulation (eg, asymptomatic hepatomegaly or persistently elevated aminotransferases). Asymptomatic patients with Wilson disease are typically diagnosed when they undergo screening because they are a blood relative of a patient with Wilson disease. (See 'Patients with symptoms and/or organ damage' below and 'Asymptomatic patients without organ damage' below.)

Patients with symptoms and/or organ damage — Copper chelating agents (ie, D-penicillamine, trientine) are first-line therapy for patients with Wilson disease who have symptoms and/or organ damage (algorithm 1). Selecting an agent is individualized and informed by published data, drug safety profile, patient comorbidities, clinical experience, drug availability, and cost. D-penicillamine has been commonly used for initial treatment [3]. However, trientine is also a reasonable option for initial therapy. In addition, we typically use trientine for patients who develop or are at risk for toxicity from D-penicillamine. Patients at risk for D-penicillamine-associated toxicity include those with kidney disease or severe thrombocytopenia (eg, platelet count <40,000/microL). (See 'Drug dosing and administration' below.)

Most patients have some improvement in symptoms and liver biochemistries in two to six months after initiating therapy. Many patients continue to improve beyond six months, with stabilization of liver synthetic function occurring somewhere between 6 and 18 months. For clinical symptoms, improvement can continue gradually for several years.

The use of chelating agents is supported by data from observational studies and clinical experience [4-16]. In a retrospective study of 231 patients with symptomatic Wilson disease, rates of improvement in liver-related symptoms and/or biochemistries were not significantly different for patients treated with D-penicillamine compared with trientine after 48 months (91 versus 93 percent) [11]. Rates of progressive liver disease were also not significantly different between the groups (2 versus 0 percent). In addition, rates of neurologic improvement were not significantly different between the groups. However, D-penicillamine was associated with lower rates of progressive neurologic symptoms (2 versus 10 percent).

Limited data suggested that chelating therapy was more effective for preventing progressive liver disease than oral zinc [17,18]. In a retrospective study including 288 patients with Wilson disease who were followed for a median of 17 years, zinc monotherapy was associated with higher rates of treatment failure (defined as increased liver biochemistries) compared with a chelating agent (16 versus 1 percent) [18]. In addition, patients who did not respond to zinc monotherapy had improvement in liver biochemistries after switching to chelating therapy.

Data from small retrospective studies suggested that trientine was effective for treating patients with adverse effects from D-penicillamine. In two studies including 41 patients with Wilson disease who did not tolerate D-penicillamine, the trientine formulation, triethylene tetramine dihydrochloride, was associated with symptomatic improvement in 34 patients (83 percent) after a mean of 49 months of follow-up [19]. Four patients (10 percent) had no change in symptoms, and one patient had progressive symptoms. Two patients were lost to follow-up.

Asymptomatic patients without organ damage — We treat asymptomatic patients without organ damage with either a chelating agent (ie, D-penicillamine or trientine) or zinc [20,21].

For patients who begin a chelating agent, we typically use maintenance dosing (ie, a lower dose than induction dosing). (See 'Drug dosing and administration' below.)

Most asymptomatic patients do not develop symptoms while on therapy.

Most studies supporting the use of zinc for asymptomatic patients involve pediatric populations who were diagnosed following screening for Wilson disease because of a positive family history [22-26]. In an observational study including 22 pediatric patients with asymptomatic Wilson disease who were treated with oral zinc therapy for 10 years, 21 patients (95 percent) had normalization of alanine aminotransferase (ALT) levels after 10 years, and no patients developed symptomatic liver disease [24].

Drug dosing and administration

D-penicillamine — D-penicillamine contains a free sulfhydryl group that functions as a copper chelating moiety. Its major effect is to remove copper from less tightly bound sites on proteins, peptides, and membranes, and promote its renal excretion. In addition, D-penicillamine may also function by other mechanisms such as stimulation of endogenous metallothionein.

D-penicillamine is absorbed rapidly from the gastrointestinal tract [27]. Its absorption is decreased by as much as 50 percent when taken with food. More than 80 percent is excreted by the kidneys. Its half-life is in the range of 1.7 to 7 hours [28].

Dosing — For adults who weigh ≥45 kg, we begin D-penicillamine with a dose of 250 to 500 mg orally once daily. We then increase the dose in 250 mg increments every four to seven days to a maximum dose of 1500 mg per day, given in two to four divided doses. For adults who weigh <45 kg and for pediatric patients, we begin with 250 mg orally once daily. We then increase the dose in 250 mg increments every four to seven days to a maximum total daily dose of 20 mg/kg (rounded to the nearest 250 mg) or approximately 1000 mg per day in two or three divided doses. Gradually increasing the dose may lower the risk of immediate adverse effects such as fever and rash, but it does not appear to lower the risk of late-onset toxicity, such as nephrotic syndrome. (See 'Adverse effects' below.)

If D-penicillamine is used long term, we usually add pyridoxine (vitamin B6) supplementation (25 to 50 mg/day) since D-penicillamine may cause pyridoxine deficiency. (See "Overview of water-soluble vitamins", section on 'Vitamin B6 (pyridoxine)'.)

For maintenance dosing, we lower the total dose to 750 to 1000 mg daily, given in two divided doses. When a biochemical response to adjusting the maintenance dose occurs, it may not be seen for up to six weeks after adjusting the dose. (See 'Patients who respond to drug therapy' below.)

We typically instruct patients to take D-penicillamine one hour before or two hours after meals because food interferes with its absorption.

Adverse effects — D-penicillamine is associated with multiple adverse effects that result in discontinuing therapy in approximately 30 percent of patients [29]. In addition, cross-reactivity to penicillin may occur. Thus, for patients with penicillin allergy, we use the drug cautiously or use an alternative agent (eg, trientine).

Adverse effects may be classified by timing of the event:

Early adverse effects – Early sensitivity reactions occur within one to three weeks of initiating therapy and include fever, rash, lymphadenopathy, neutropenia, thrombocytopenia, and proteinuria. For patients who develop early side effects, we discontinue D-penicillamine immediately and initiate an alternative agent such as trientine. (See 'Trientine' below.)

Late adverse effects – Later reactions develop after months to years of therapy and include the following (see 'Drug monitoring' below):

Exacerbated neurologic disease – For patients with predominantly neurologic disease, initiating D-penicillamine may worsen neurologic symptoms in approximately 20 percent of such patients [30-32]. In addition, some patients develop new neurologic symptoms. In a series of 143 patients with Wilson disease, 16 patients (23 percent) with neurologic disease had worsening neurologic status with a median time of onset of 2.3 months after initiating treatment [30]. Exacerbation of neurologic symptoms may be related to mobilization of liver copper stores that increases brain copper exposure or to the development of intracellular copper complexes.

For patients who develop worsening neurologic symptoms (other than loss of taste), we typically discontinue D-penicillamine and begin an alternative agent (eg, trientine or zinc).

Kidney toxicity – Kidney toxicity is typically manifested by proteinuria, or less commonly, crescentic glomerulonephritis [33]. We discontinue D-penicillamine if the patient develops nephrotic syndrome. Proteinuria typically resolves several months after stopping the drug [34].

Bone marrow toxicity – Bone marrow toxicity with thrombocytopenia or aplastic anemia is rare but may not be reversible.

Dermatologic effects – Skin changes include elastosis perforans serpiginosa, lichen planus, aphthous stomatitis, bullous pemphigoid, and pseudoxanthoma elasticum [35-38].

Other side effects – Other late reactions include anti-GBM (Goodpasture) disease, myasthenia gravis, polymyositis, hepatotoxicity, hepatic siderosis/iron overload, loss of taste, and a lupus-like syndrome characterized by hematuria, proteinuria, and a positive antinuclear antibody [39].

Gastrointestinal side effects may occur at any time during therapy and include nausea, vomiting, and anorexia. These symptoms are dose-related signs of gastric irritation, and they improve with reducing the dose.

Drug monitoring — We obtain a complete blood count, urinalysis, and serum creatinine after the first week and then once a month during the first three months; at three-month intervals until target urinary copper levels are achieved; and twice per year thereafter.  

We discontinue D-penicillamine for patients who develop leukopenia (white blood cell count <3000/microL), neutropenia (neutrophil count <2000/microL), thrombocytopenia (platelet count <80,000/microL if pretreatment baseline value was ≥150,000/microL), or if a steady decline over three successive tests is observed, even though the counts remain above the threshold value for discontinuation. Monitoring patients with cirrhosis who are treated with D-penicillamine is discussed below. (See 'Patients with cirrhosis' below.)

We obtain iron studies and ferritin if there is a decrease in hemoglobin or concern for overtreatment (typically after many years of therapy).

We measure 24-hour urine for protein if urinalysis shows new or worsening proteinuria. We typically discontinue D-penicillamine if proteinuria exceeds 2+ on a dipstick and is confirmed with 24-hour urine for protein, if red cell or white casts are observed at microscopic examination of the urine, or if more than 10 red cells are seen per high-power field. For such patients, we switch to trientine or zinc. However, some hepatologists continue D-penicillamine if quantitative proteinuria does not exceed 1 g/day and is not trending upward. For patients with proteinuria exceeding 2 g/day or a down-trending glomerular filtration rate, we permanently discontinue D-penicillamine. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Detection and measurement of total urinary protein excretion'.)

We assess adherence to the drug regimen by measuring 24-hour urinary copper excretion. However, a rise in urinary copper after previously achieving the target level may be related to higher dietary copper intake or lack of adherence to the drug regimen. History from the patient or caregivers can help determine which of these etiologies is likely. In addition, when the dose of D-penicillamine is increased, the urinary copper excretion may also increase and does not reflect nonadherence. This occurs because binding of copper to D-penicillamine is stoichiometric, thus, the amount of copper excreted in the urine will increase with increasing dosing of D-penicillamine.

Trientine — Trientine is a copper chelator that is available in several formulations including triethylene tetramine dihydrochloride (also referred to as trientine hydrochloride) and trientine tetrahydrochloride [40]. Trientine differs from D-penicillamine by lacking sulfhydryl groups, and it chelates copper by forming a stable complex with its four constituent nitrogens. Trientine functions principally by removing copper from less strongly bound sites on proteins and membranes and by increasing renal copper excretion. In addition, the non-absorbed drug may block intestinal absorption of copper. (See 'Dosing' below.)

On a mole for mole basis, more copper is excreted in the urine following use of D-penicillamine than trientine. However, the potential action of non-absorbed trientine to block dietary copper uptake allows for achieving goals of therapy with comparable dosages. (See 'Treatment goals' above.)

The pharmacokinetics of trientine have not been well studied. It is poorly absorbed; only 1 percent of the ingested amount (and 8 percent of its principal metabolite, acetyltrien) is excreted in the urine. The amount of iron, zinc, and copper chelated correlates with the amount of trientine in the urine [41].

Dosing — For adults, the initial dose of triethylene tetramine dihydrochloride is 15 to 20 mg/kg per day (up to a maximum dose of 1500 mg) in two or three divided doses. Maintenance dosing is approximately 15 mg/kg per day (up to a maximum dose of 1500 mg) given in two or three divided doses.

For pediatric patients, the initial dose is 20 mg/kg per day, rounded to the nearest 250 mg, given in two or three divided doses. Maintenance dosing is 10 to 15 mg/kg per day, given in two or three divided doses.

We instruct patients to take trientine ideally one hour before or two hours after meals. The drug is not stable at high temperatures and requires refrigerated storage.

We do not use once daily trientine dosing, but it has been studied for increasing adherence and ease of maintenance dosing [42]. Further studies are needed to confirm efficacy and safety of this dosing regimen.

Another formulation, trientine tetrahydrochloride, has been approved by the US Food and Drug Administration (FDA) for treating adults with stable disease in the maintenance phase of therapy [43-45]. Doses of trientine formulations are generally not equivalent (except if expressed as trientine base), and local product labeling should be consulted.

We advise patients to avoid taking trientine with iron supplementation because trientine chelates iron and forms nephrotoxic complexes. If oral iron supplementation is needed, it may be given for a short course and with at least two-hour intervals between administration of trientine and iron.

Adverse effects — Adverse effects related to trientine use include pancytopenia (rare), colitis, hemorrhagic gastritis, loss of taste, rash, reversible sideroblastic anemia, and possibly hepatic iron overload with prolonged, high-dose therapy [46-49]. Excess iron may increase the risk of liver toxicity [49]. Overall, trientine seems to have fewer side effects than D-penicillamine. Worsening of neurologic symptoms may occur with trientine [11].

Drug monitoring — We measure complete blood count, urinalysis, and serum creatinine after the first week and then once a month during the first three months; then at three-month intervals until target urinary copper levels are achieved; and twice per year thereafter. (See 'Assessing response to therapy' below.)

We measure 24-hour urine for protein if urinalysis shows new or worsening proteinuria.

Zinc — Oral zinc interferes with the absorption of copper by inducing enterocyte metallothionein (an endogenous chelator of metals), which has a greater affinity for copper than for zinc. Metallothionen binds luminal copper and thereby prevents it from entering into the circulation [50]. The bound copper is excreted in stool with normal turnover of enterocytes. Copper from salivary and gastric secretions is also bound, thereby further enhancing a negative copper balance [51]. Zinc may also induce hepatocellular metallothionein [52,53].

Dosing — Zinc salts are available in several formulations that inhibit copper absorption similarly. However, the formulations differ in their absorption and tolerability. Zinc acetate has the best absorption. Zinc gluconate is an alternative, and it is more tolerable than zinc sulfate with respect to gastrointestinal side effects.  

Dosing is in milligrams of elemental zinc. The total daily dose of zinc for adults is 150 mg, given in three divided doses. Twice daily dosing is an alternative dosing regimen for patients who cannot adhere to three times daily dosing [22]. However, we do not use once daily dosing because it is not effective.

We advise patients to avoid eating for at least two hours before and for one hour after taking zinc because food interferes with zinc absorption.  

Adverse effects — The most common adverse effect of zinc is gastric irritation leading to dyspepsia and/or gastritis. Approximately 30 percent of patients using zinc develop gastrointestinal side effects, and some patients require switching to an alternative zinc salt or to a chelating agent [54]. Uncommon adverse effects associated with zinc include worsening liver disease, worsening neurologic disease, and elevated serum amylase and lipase in the absence of acute pancreatitis [18,55,56].

Assessing response to therapy — We monitor response to initial therapy by measuring 24-hour urinary copper excretion and by assessing for clinical and biochemical improvement [57]. Most patients require at least six months of drug therapy to achieve these goals:

Urinary copper excretion – We measure 24 urinary copper excretion within a month after achieving the goal dose of therapy. The pretreatment levels for urinary copper excretion may exceed 100 mcg/24 hours (1.6 micromol/24 hours) in symptomatic patients, and after initiating chelation (D-penicillamine or trientine), it may increase to above 1000 to 2000 mcg/24 hours (16 to 31 micromol/24 hours). The rate of copper excretion falls as copper stores become depleted. After 6 to 12 months of therapy, levels of urinary copper usually fall to below 500 mcg/24 hours (8 micromol/24 hours).

For patients on zinc therapy, urinary copper begins to decline from pretreatment levels and should not exceed 100 mcg/24 hours (1.6 micromol/24 hours) over time.

Biochemical testing – We typically measure serum aminotransferases, total bilirubin and international normalized ratio (INR), every three months during treatment initiation, or more frequently in those with elevated pretreatment values.

Symptoms – We monitor patients for symptomatic improvement.

When target urinary copper levels are achieved, we reduce the frequency of measuring laboratory studies to every 6 to 12 months. (See 'Monitoring during maintenance' below.)

We transition patients who meet the following criteria to maintenance therapy (see 'Patients who respond to drug therapy' below):

For patients on D-penicillamine or trientine, 24-hour urinary copper excretion <500 mcg (8 micromol)/24 hours. For patients on zinc, 24-hour urinary copper excretion <100 mcg (1.6 micromol)/24 hours

Normal (or near normal) serum aminotransferases

Symptomatic improvement

SUBSEQUENT MANAGEMENT

Patients who respond to drug therapy

Transitioning to maintenance therapy — Patients with Wilson disease require lifelong therapy unless the patient undergoes liver transplantation [12] (see 'Nonresponders' below). The goals of maintenance therapy are to prevent copper from reaccumulating in tissue and to prevent progressive liver disease and acute liver injury.

Most patients require a minimum of 6 to 18 months of initial treatment to achieve disease remission. However, some patients may require up to five years of induction therapy. Prior to transitioning to maintenance therapy, patients should have symptomatic improvement, normal (or near normal) serum aminotransferases, and 24-hour urinary copper excretion within target ranges for their specific therapy (<500 mcg [8 micromoles] per day for D-penicillamine or trientine, and <100 mcg [1.6 micromoles] per day for those on zinc).

Selecting maintenance therapy is informed by the patient's existing drug regimen, drug safety and efficacy, and patient preferences. Maintenance therapy options include either a lower dose chelating agent (ie, reducing the dose by approximately one-third) or zinc. For patients on a lower dose chelator, there is increasing use of trientine for long-term maintenance because it has fewer side effects than D-penicillamine. (See 'Drug dosing and administration' above.)

Data from randomized trials suggested that trientine tetrahydrochloride was effective for preventing copper reaccumulation after initial chelation therapy. In an open-label trial including 53 patients with Wilson disease who were initially stabilized with D-penicillamine, there were no significant differences in serum levels of non-ceruloplasmin-bound copper or in clinical response at 24 and 48 weeks for patients treated with trientine tetrahydrochloride compared with D-penicillamine [45]. In addition, trientine tetrahydrochloride was well tolerated with no serious adverse events.

Data from observational studies suggested that zinc salts were effective for maintaining copper balance [54,58]. In a study including 60 patients with Wilson disease who had achieved copper detoxification with a chelating agent, zinc acetate (50 mg dose three times daily) was associated with adequate copper balance in 64 patients (91 percent) [58].

Monitoring during maintenance — For patients on maintenance therapy, monitoring is important to detect loss of response or nonadherence before progressive liver disease develops.

For long-term monitoring, we perform a physical examination and measure the following every six months:

Serum copper

Serum ceruloplasmin

Liver biochemistries – Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

International normalized ratio (INR)

Complete blood count

Urinalysis (for patients on D-penicillamine or trientine therapy)

We also measure 24-hour urinary excretion of copper every 12 months or more frequently if we adjust the drug dose or suspect nonadherence.

Nonresponders — For patients who do not respond to initial therapy despite adhering to dietary and drug regimens in the absence of comorbid liver disease, other therapeutic options include [59]:

Combination therapy – For patients who do not respond or worsen with D-penicillamine or trientine alone, adding zinc treatment along with the chelating agent (referred to as combination therapy) may be an option [60]. The complementary actions of zinc and chelating agents (preventing copper absorption and promoting copper removal, respectively) provide a physiologic rationale for using combination therapy. However, data from clinical trials are lacking.

We instruct patients on combination therapy to take zinc at least twice daily and several hours apart from D-penicillamine. The combination of zinc with D-penicillamine or trientine may increase the risk for developing sideroblastic anemia if used chronically as it may lead to more copper depletion (ie, overtreatment). Thus, we monitor hemoglobin levels every three to six months along with monitoring liver biochemistries.

Liver transplantation – Indications for liver transplantation in patients with Wilson disease include acute liver failure, decompensated cirrhosis unresponsive to drug therapy, and cirrhosis complicated by hepatocellular carcinoma [61,62]. (See "Liver transplantation for hepatocellular carcinoma" and 'Special populations' below.)

Liver transplantation cures Wilson disease; thus, patients do not resume therapy for Wilson disease after transplantation. In addition, long-term outcomes following liver transplantation for Wilson disease are excellent [62-64]. In a series of 27 adults with Wilson disease who underwent liver transplantation, one- and five-year patient survival rates were 88 and 83 percent, respectively [62]. In an earlier database study including 170 children and 400 adults with Wilson disease who received a liver transplant, there were no significant differences in pediatric compared with adult patient survival rates (one-year survival: 90 versus 88 percent, and five-year survival: 89 versus 86 percent) [63]. (See 'Pediatric patients' below.)

Whether liver transplantation is indicated for treating neurologic Wilson disease is uncertain [11,65-68]. Although data from case series suggested that liver transplantation was associated with some neurologic improvement, patients with persistent neuropsychiatric disease may have difficulty adhering to lifelong immunosuppression. In addition, patient survival rates may be lower in patients with neurologic involvement. In an observational study including 18 patients with Wilson disease who underwent liver transplantation for severe neurologic symptoms (eg, dystonia, parkinsonism), patient survival rates at one, three, and five years were 88, 72, and 72 percent, respectively [65].

Investigational agents – Another chelating agent, ammonium tetrathiomolybdate (TTM), interferes with copper absorption when the medication is given orally with meals, and binds plasma copper [69,70]. Preliminary data suggested that ammonium TTM improved neurologic symptoms with a lower risk of worsening neurologic symptoms compared with trientine [71]. However, clinical trials involving an alternative, stabilized form of TTM were halted, and neither formulation is commercially available [72].

PROGNOSIS — The prognosis in patients with Wilson disease who adhere to lifelong therapy is generally good. The natural history, overall survival, and risk of hepatocellular carcinoma in patients with Wilson disease are discussed separately. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Disease course'.)

SPECIAL POPULATIONS

Patients with acute liver failure — We evaluate patients with acute liver failure related to Wilson disease for urgent liver transplantation, and we manage such patients at a liver transplant center. General measures for patients with acute liver failure, including monitoring and nutritional support, are discussed separately. (See "Acute liver failure in adults: Management and prognosis", section on 'General management'.)

Patients with acute liver failure often require liver transplantation. The goal of initial therapy is removing copper rapidly and stabilizing the patient while awaiting transplantation for definitive treatment. Several interventions are available for removing copper rapidly, including apheresis and renal replacement therapy [73]. Net copper removal is proportional to plasma concentration and can reach 12 mg per session. In addition, most patients with acute liver failure related to Wilson disease have hemolytic anemia. Copper ions leak from necrotic hepatocytes into the circulation and cause lysis of red blood cells. Therapies to reduce hemolysis and prevent kidney injury related to copper and copper complexes include plasmapheresis, plasma exchange, renal replacement therapy, and use of a molecular absorbant recirculating system (MARS) device [74-78].

The clinical presentation of acute liver failure related to Wilson disease is discussed separately. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Liver disease'.)

Patients with cirrhosis — Patients with cirrhosis may experience improvement of liver disease with chelating therapy, and these clinical improvements (eg, resolution of ascites, fibrosis regression, and reduction in liver stiffness measured by elastography) may occur beyond six months of initiating treatment.

Some patients with cirrhosis and portal hypertension have leukopenia and thrombocytopenia at baseline. Thus, if D-penicillamine is initiated, we monitor complete blood count every month at first, then two to four times per year afterwards. We discontinue D-penicillamine for patients with cirrhosis who develop leukopenia (white blood cell count <3000/microL), neutropenia (neutrophil count <2000/microL), or thrombocytopenia (platelet count <30,000/microL). (See 'D-penicillamine' above.)

General measures for patients with cirrhosis including management of complications (eg, hepatic encephalopathy) are discussed in detail separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

Pregnancy and lactation — We continue drug therapy for Wilson disease during pregnancy because stopping therapy has been associated with risk of acute liver failure, clinical deterioration, and maternal mortality [79].

Adjusting drug therapy – Adjusting drug therapy during pregnancy is informed by the relative drug safety, risks of interrupting therapy, clinical experience, available data, and society guidelines [21]:

D-penicillamine – We continue D-penicillamine during pregnancy because it is generally safe. However, D-penicillamine has rarely been associated with cutaneous and thyroid abnormalities in the offspring of mothers exposed to the drug during pregnancy [80,81].

We typically lower the D-penicillamine dose by 25 to 50 percent of the pre-pregnancy dose to reduce risk to the fetus during the first trimester and to promote better wound healing for mothers who have a cesarean delivery or episiotomy. We monitor patient symptoms and measure liver biochemistries once during each trimester to confirm that the patient is tolerating dose adjustment. We continue the lower maintenance dose for two to three weeks after delivery, and then resume the pre-pregnancy dose.

Trientine – We continue trientine during pregnancy based on clinical experience, although published data on the safety of trientine during pregnancy are limited. We typically lower the trientine dose by 25 to 50 percent of the pre-pregnancy dose. We monitor patient symptoms and measure liver biochemistries once during each trimester to confirm that the patient is tolerating dose adjustment. We continue the lower maintenance dose for two to three weeks after delivery, and then resume the pre-pregnancy dose.

Zinc – We continue zinc during pregnancy without dose adjustment. Studies in pregnant patients suggested that zinc salts were not associated with increased risk of fetal abnormalities [82].

Lactation – D-penicillamine is excreted in mother's milk, whereas it is unknown whether the trientine is excreted in mother's milk [83]. In addition, the human milk concentration of copper may be reduced in patients with Wilson disease [83,84]. Thus, the amount of copper in mother's milk may be inadequate to meet the daily requirements of the developing newborn. We advise mothers to discuss the possible risks related to lactation with their newborn's clinician who may monitor the newborn for copper deficiency. (See "Laboratory and radiologic evaluation of nutritional status in children", section on 'Minerals'.)

Patients undergoing elective surgery — We continue drug therapy for patients with Wilson disease who are undergoing elective surgery because stopping therapy has been associated with acute liver failure and liver decompensation. (See 'Pregnancy and lactation' above.)

For patients on chelating therapy, we typically lower the dose by 25 to 50 percent prior to surgery because chelating agents have been associated with impaired wound healing [21]. We resume the pre-surgery dose after surgical wounds have healed.

Pediatric patients — We provide nutritional counseling for pediatric patients and their caregivers. Copper and zinc are required for the metabolic and developmental needs of pediatric patients. In addition, we monitor copper dietary intake (eg, infant formula, solid foods) to avoid excess copper exposure.

Drug dosing for pediatric patients is generally informed by patient age and/or weight:

Age <5 years – There is no consensus on optimal timing for initiating drug therapy for young children with Wilson disease [25]. Factors informing the decision include patient symptoms and liver biochemistries, potential adverse effects of drug therapy (eg, copper deficiency), and patient/caregiver preferences. When drug therapy is indicated for pediatric patients <5 years of age, we typically use zinc. The total daily dose of zinc is 50 mg, given in two divided doses, although published data on the optimal dose for younger children are lacking [85].

Other challenges to initiating drug therapy in very young children include risk of copper deficiency with therapy and lack of 24-hour urinary copper monitoring to guide therapy (ie, patients are not yet toilet trained) [86].

Age ≥5 years – Weight-based dose adjustments for D-penicillamine and trientine are discussed above. (See 'D-penicillamine' above and 'Trientine' above.)

For older pediatric patients weighing ≥50 kg, the total daily dose of zinc is 150 mg, given in three divided doses. Twice daily dosing is an alternative dosing regimen for patients who cannot adhere to three times daily dosing [22]. For older pediatric patients who weigh <50 kg, the total daily dose is 75 mg, given in three divided doses [85].

For pediatric patients, elevated serum aminotransferases do not necessarily indicate nonadherence because up to one-third of pediatric patients continue to have mildly elevated aminotransferases despite adequate treatment [87]. However, for patients in whom the aminotransferases normalized with therapy, new elevations in liver biochemistries warrant further investigation.

Patients with neuropsychiatric symptoms — For patients with neuropsychiatric symptoms (eg, tremor, dystonia), restoring normal copper balance with drug therapy typically results in symptomatic improvement. However, some patients may require additional therapies (eg, pharmacologic, physical, and/or speech therapy) to alleviate neuropsychiatric symptoms [88-90].

Management of specific neurologic and psychiatric conditions is discussed separately:

Chorea – (See "Overview of chorea", section on 'Management of chorea'.)

Dystonia – (See "Treatment of dystonia in children and adults".)

Gait abnormalities/ataxia – (See "Overview of cerebellar ataxia in adults", section on 'Management'.)

Parkinsonism – (See "Nonpharmacologic management of Parkinson disease".)

Tremor – (See "Overview of tremor", section on 'Treatment'.)

Seizures – (See "Overview of the management of epilepsy in adults" and "Seizures and epilepsy in children: Initial treatment and monitoring".)

Bipolar disorder – (See "Bipolar major depression in adults: Choosing treatment" and "Pediatric bipolar disorder: Overview of choosing treatment".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited liver disease".)

SUMMARY AND RECOMMENDATIONS

General measures – General measures for all patients with Wilson disease include (see 'General measures' above):

Avoiding foods with high copper content. A list of food mineral content is available on the United States Department of Agriculture website.

Age-appropriate immunizations, in addition to vaccination for hepatitis A virus and hepatitis B virus for patients without serologic evidence of immunity. (See "Immunizations for adults with chronic liver disease".)

We advise patients to refrain from alcohol and, in particular, avoid heavy alcohol use (ie, >14 drinks per week or >4 drinks on a given day for males and >7 drinks per week or >3 drinks on a given day for females).

Hepatology consultation for long-term management.

Goals of therapy – Goals of therapy are to detoxify excess copper in tissue, prevent copper from further accumulation in tissue, improve symptoms, and improve liver function. (See 'Treatment goals' above.)

Pretreatment testing – Prior to initiating pharmacologic therapy, we obtain or review the following studies (see 'Pretreatment evaluation' above) :  

24-hour urinary copper excretion

Ceruloplasmin

International normalized ratio (INR)

Iron studies and ferritin

Serum aminotransferases – Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

Serum copper

Serum creatinine

Serum sodium

Total bilirubin

Uric acid

Urinalysis

Initial therapy Selecting an initial therapy is informed by whether the patient has symptoms and/or evidence of organ damage related to copper accumulation (algorithm 1) (see 'Selecting initial therapy' above):

Patients with symptoms and/or organ damage – For patients with symptoms and/or organ damage, we suggest initial therapy with a D-penicillamine rather than trientine or oral zinc (Grade 2C). Observational data and clinical experience suggested that D-penicillamine was effective for improving symptoms and liver function in addition to preventing disease progression. Trientine is a reasonable option for initial therapy, whereas zinc may be less effective.

Asymptomatic patients without organ damage – For patients without symptoms or organ damage, we use drug therapy rather than expectant management (Grade 2C). Drug therapy prevents additional copper from accumulating in tissues and prevents the development of symptoms.

Maintenance therapy – Criteria for transitioning to maintenance therapy include symptomatic improvement, normal (or near normal) serum aminotransferases, and 24-hour urinary copper excretion <500 mcg (8 micromoles)/24 hours for patients on D-penicillamine or trientine, and <100 mcg (1.6 micromol)/24 hours for patients on zinc. (See 'Subsequent management' above.)

Patients require maintenance drug therapy indefinitely. Discontinuing therapy may lead to acute liver failure and/or progressive liver disease. Selecting maintenance therapy is informed by the patient's existing drug regimen, drug safety and efficacy, and patient preferences. Maintenance therapy options include either a lower dose chelating agent (ie, reducing the dose by approximately one-third) or zinc.

Special populations – Some patients develop complications or have other indications for modifying therapy. A discussion of these special populations includes:

Patients with acute liver failure – (See 'Patients with acute liver failure' above.)

Patients with cirrhosis – (See 'Patients with cirrhosis' above.)

Pregnancy and lactation – (See 'Pregnancy and lactation' above.)

Patients undergoing elective surgery – (See 'Patients undergoing elective surgery' above.)

Pediatric patients – (See 'Pediatric patients' above.)

Patients with neuropsychiatric symptoms – (See 'Patients with neuropsychiatric symptoms' above.)

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Topic 3591 Version 35.0

References

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