Gastroenterology Hepatology

Hereditary hemochromatosis

How can I be sure that the patient has Wilson disease?

Overview

Wilson disease (WD) is an autosomal recessive disorder that results from mutations in the ATP7B gene located on the long arm of chromosome 13. More than 500 mutations have been identified. ATP7B protein is responsible for both hepatic copper incorporation into ceruloplasmin and for transport for biliary copper excretion. Decreased ATP7B function results in reduced biliary copper excretion with increased copper accumulation in hepatic and, afterwards, in extra-hepatic tissues that leads to the clinical features of WD. WD has been reported in virtually all populations and has a global incidence of 1 in 30,000.

What signs and symptoms are usually found?

Symptoms of WD usually appear in the first 4 decades of life, with the majority of cases occurring between 5 and 35 years of age, although it has been reported in patients as early as 3 and as late as 72 years of age.

The WD phenotype can be highly variable, with a clinical spectrum that ranges from entirely asymptomatic to chronic liver disease and portal hypertension to acute liver failure. In general, a great deal of symptomatic overlap exists with many types of acute or chronic hepatitis.

WD can also present with a dominant picture of neurological or psychiatric symptoms. Neurologic and psychiatric disease presents typically in the late 2nd or 3rd decades of life and may either present alone or in combination with liver disease.

Hepatic Disease

Many patients have liver test abnormalities alone. Others may present with varying signs and symptoms of portal hypertension representing end-stage liver disease and cirrhosis. Stigmata of chronic liver disease and portal hypertension due to Wilson disease include jaundice, ascites, coagulopathy, and hepatic encephalopathy.

Neurologic and psychiatric disease

Neurologic features may be insidious and progress over months and years. Neurologic characteristics include tremor, dystonia, Parkinsonian-like cogwheel rigidity, drooling, and dysarthria. Patients may present with neurologic symptoms prior to the recognition of any liver abnormalities. Psychiatric symptoms commonly associated with the disease include subtle personality changes, behavioral problems (younger patients), emotional lability, affective disorder, major depression, dysthymia, anxiety, and psychosis.

Other organ involvement

Multiple other organ systems may be affected: ophthalmologic findings such as Kayser-Fleischer rings (Figure 1) may be present in approximately 50% of those with liver presentation and in more than 95% of those with neuropsychiatric symptoms and sunflower cataracts (rare); skeletal involvement, including osteopenia and arthritis; endocrine abnormalities, including hypoparathyroidism; reproductive infertility and miscarriage risk; and kidneys, including aminoaciduria and nephrolithiasis.

A tabular or chart listing of features and signs and symptoms

Classical features, signs, and symptoms

Common

Kayser-Fleischer rings (best visualized on slit lamp exam)

Hepatomegaly

Splenomegaly

Ascites

Jaundice

Hepatitis

Coagulopathy

Acute liver failure

Hemolytic anemia

Renal tubular dysfunction

Movement disorders: tremor, Parkinsonian-like rigidity, handwriting changes

Psychiatric disturbance: personality disturbance, depression

Less Common

Pancreatitis

Myositis

Cardiac arrhythmias

Sunflower cataracts

Autonomic dysautonomia

Lunulae ceruleae

How can I confirm the diagnosis?

Diagnosis

The diagnosis should be based on findings in the patients' history, family history, physical examination (including slit lamp eye exam), laboratory tests (see below), liver biopsy histology, radiographic findings, and molecular genetic testing for ATP7B mutation analysis. Classically, the presence of K-F rings and either a low ceruloplasmin or typical neurologic disease is diagnostic. Although K-F rings are very common in patients with neurologic disease (~98%), they are seen in only approximately half of patients with hepatic presentation.

Expected results of diagnostic studies

First-tier investigations

  • Liver tests may show transaminase and bilirubin elevations with an inappropriately low alkaline phosphatase for degree of cholestasis.

  • In acute liver failure: alkaline phosphatase: total bilirubin ratio of <4 and AST:ALT ratio >2.2 (combined sensitivity and specificity approaching 100%).

  • Prolonged prothrombin time (INR) showing hepatic synthetic dysfunction with advancing liver disease.

  • Complete blood cell count may indicate coombs-negative hemolytic anemia; leukopenia and/or thrombocytopenia from hypersplenism.

  • Serum ceruloplasmin level is depressed (<20 mg/dL) in 95% of those with liver presentation, although less reliable in the setting of acute liver failure.

  • Slit lamp eye exam may show Kayser-Fleischer rings in 50% in those with liver symptoms and in more than 95% of those with neuropsychiatric disease or sunflower cataracts (rare).

  • Serum copper usually low or normal but may be above 200 µg/dL in acute liver failure.

  • Hypouricemia

  • 24-hr urinary copper quantification elevated above 100 µg/24hr, but values above 60 µg/24hr warrant further investigations.

  • Aminoaciduria resembling Fanconi syndrome.

Second-tier investigations

  • Liver biopsy: histology: hepatic steatosis, hepatocyte necrosis, apoptosis, and varying degrees of fibrosis

  • Electron microscopy: mitochondrial dilated cristae; lysosomal copper deposition

  • Liver copper quantification >250 µg/g dry weight; however, values above 75 µg/g warrant further testing and can overlap with cholestatic liver disease.

Other investigations

MRI/CT brain: basal ganglia, pons or thalamus changes.

– A scoring system to determine the need for further evaluation for WD based on a combination of clinical symptoms, laboratory testing, and mutational analysis was developed in Leipzig, Germany, in April 2002 and, subsequently, has been validated.

KF rings present=2, absent=0

Neuropsychiatric symptoms (or brain MRI) present=2, absent=0

Coombs negative hemolytic anemia present=1, absent=0

24-hr urinary copper normal=0, 1-2x normal=1, >2x normal=2

Hepatic quantitative copper normal=-1, up to 5x normal=1, >5x normal=2

Rhodanine positive (positive histochemical staining) hepatocytes present=1, absent=0

Serum ceruloplasmin (mg/dL) normal=0, 10-20=1, <10=2

Mutational analysis homozygous mutation=4

heterozygous mutation=1

no mutation=0

Cumulative score assessment

4 or greater: WD diagnosis highly likely

2-3: WD diagnosis probable, more investigation required

0-1: WD diagnosis unlikely

See Figure 2 (Algorithmic approach in a patient with suspected Wilson disease).

What other diseases, conditions, or complications should I look for in patients with Wilson disease?

Differential diagnosis

Pathologic liver conditions such as nonalcoholic fatty liver disease, viral hepatitis and autoimmune hepatitis, or any unexplained liver disease may mimic WD and should be excluded, particularly if lack of response to a particular therapy is seen. In children, a diagnosis of mitochondrial disease or fatty acid oxidation should be considered. Neurologic conditions such as Parkinson disease and non-Wilson hepatolenticular degeneration due to hypermanganism should be considered.

Risk factors

WD has been described in virtually all ethnic groups. Risk factors for WD include the diagnosis of WD in a family member, particularly 1st-degree relatives, liver disease confluent with neuro/psychiatric disease, or any unexplained liver disease. Affected females and children are more common among the 5% that present with acute liver failure.

Complications

Complications largely relate to end-stage liver disease and portal hypertension. However, neurologic or psychiatric symptoms may also predominate. Screening for esophageal varices via endoscopy and for hepatocellular carcinoma by liver sonogram is recommended in those patients who develop cirrhosis.

Variceal hemorrhage

Splenomegaly

Hepatopulmonary syndrome

Portopulmonary syndrome

Hepatorenal syndrome

Hepatic encephalopathy

Hepatocellular carcinoma

Parkinsonian-like rigidity

Worsening neurological symptoms due to progressive disease or at the start of treatment (dystonia, dysarthria, oropharyngeal (transfer) dysphagia, hypersalivation, tremors)

Contractures as a result of prolonged dystonia

Prognosis

A prognostic index may be helpful in determining which patients that present with advanced liver disease are most likely to respond to medical therapy and which should be referred for liver transplant. One WD prognostic scoring system (0-20) devised by the group at King's College, predicted a favorable response in newly diagnosed patients to chelation therapy in patients who had cumulative scores of 11 and less. Higher scores were associated with higher mortality and those requiring liver transplantation. (See Table I)

WD accounts for approximately 0.6% of all liver transplants in North America. Outcomes for children and adults with hepatic disease (excluding WD acute liver failure) have expected 5-year patient survival curves of 100% and 90%, respectively; which are better than transplantation for other etiologies. Patients with concurrent neurologic disease have less positive outcomes but may expect improvement in symptoms post transplant.

Generally, the prognosis is good. A timely diagnosis along with medication adherence may stabilize and even reverse the pathologic course in patients with active liver disease, including those with advanced fibrosis. In treated asymptomatic patients, the disease should remain clinically silent unless therapy is discontinued. Neurological and psychiatric disease also may stabilize and improve for years after the initiation of treatment.

What is the right therapy for the patient with Wilson disease?

N/A

What is the most effective initial therapy?

All patients with an established WD diagnosis regardless of presentation require life-long therapy. However, the initial choice of therapy may differ as it is governed by the clinical picture. Medications useful in the armamentarium for the treatment of WD are chelators such as d-penicillamine and trientene and also zinc compounds that interfere with gastrointestinal tract copper uptake.

Symptomatic patients with either or both hepatic or neurologic disease require therapeutic dose chelator plus zinc therapy. Chelation therapy should be continued during pregnancy at reduced doses; pregnant patients tolerating zinc monotherapy do not need to change their doses.

Asymptomatic patients, including those who are presymptomatic and have been diagnosed by genetic mutational analysis, should begin at the maintenance dose chelator or zinc therapy dosages.

Patients with WD acute liver failure (ALF) should be evaluated and considered for emergent listing for liver transplantation. In this category, marked hemolysis and renal dysfunction require early initiation of hemofiltration, albumin dialysis, exchange transfusion or plasmapharesis, or molecular adsorbents recirculating system (MARS) to control volume overload and lower circulating toxic serum copper.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

Initial chelator or zinc therapy

Medical therapy in affected patients (excluding those with ALF) is initiated at a low dose and gradually increased as tolerated.

Penicillamine: 20 mg/kg/day to maximum dose of 2 g/day divided BID-QID

Trientene: 20 mg/kg/day to maximum dose of 1500 mg/day divided TID-QID

(Pregnant patients should be dosed not more than 10 mg/kg/day for both penicillamine and trientine.)

Zinc: Adults 150 mg/day divided TID; Children (<50kg) 75 mg/day divided TID

Maintenance therapy

Life-long therapy is continued at reduced dosages, depending on clinical response (see below):

Penicillamine: 15 mg/kg/day to maximum dose of 2 g/day divided BID-QID

Trientene: 15 mg/kg/day to maximum dose of 1500 mg/day divided TID-QID

Zinc: Adults 75-150 mg/day divided TID; Children (<50kg) 50-75 mg/day divided TID

Adjunct therapy

Antioxidants such as vitamin E and curcumin have been shown to reduce oxidant injury in experimental animal models and have been suggested as potential add-on therapy to standard medications regimens.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

What side effects or complications should I expect from therapy?

Medical side effects

Penicillamine: fever, skin rash, lupus-like reactions, bone marrow suppression, nephrotic syndrome, colitis, elastosis perforans serpiginosa (EPS), progeria.

Trientene: sideroblastic anemia, colitis, lupus-like reaction

Zinc salts: dyspepsia, biochemical (nonpancreatitis) elevation of amylase and lipase

Listing of these, including any guidelines for monitoring side effects.

N/A

How should I monitor the patient with Wilson disease?

In symptomatic disease, the aim should be to achieve negative copper balance with improvement in clinical and biochemical parameters. In successfully treated patients, a lag time of up to 12 months may be seen before biochemical studies trend toward the normal range.

Neurologic and/or psychiatric disease may transiently worsen within the first month of starting therapy, ostensibly attributed to the mobilization of hepatic copper stores that leads to elevated brain copper levels. The addition of adjunctive antioxidant therapy may be of symptomatic help.

Patients on chelator therapy should have serial 24-hour urine quantitative copper collection monitoring continued until the results are in the 250 to 500µg/24-hour range. When the urine copper is reliably in this range, switching to maintenance dose therapy may begin.

Other treatment goals include a free serum copper (ceruloplasmin multiplied by 3 minus serum copper) in the 5 to 15 µg/dL range. Monitoring for signs of over chelation include complete blood cell count for hypochromic, microcytic anemia, and leukopenia. Serial neurologic examinations should be done for patients with neurologic involvement. Re-biopsy of the liver should be performed if there is a question of treatment failure or concurrent liver disease.

What's the evidence?

Ferenci, P, Caca, K, Loudianos, G. "Diagnosis and phenotypic classification of Wilson disease". Liver Intl. vol. 23. 2003. pp. 139-42.

(This work represents expert concensus regarding the formulation of a diagnostic score based on indices that help clinicians consider and/or strengthen the certainty of a WD diagnosis. Subsequently, the score has been validated in other studies.)

Nicastro, E, Ranucci, G, Vajro, P. "Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease". Hepatology. vol. 52. 2010. pp. 1948-56.

(This work demonstrates the importance of suspecting a WD diagnosis in young affected patients even though they often lack classical WD findings such as K-F rings or neurologic disease. However, in this cohort, other tests such as ceruloplasmin, quantitative liver copper values, molecular testing, and the WD diagnostic scoring system appear to be accurate.)

Dhawan, A, Taylor, RM, Cheeseman, P. " Wilson’s disease in children: 37-year experience and revised King’s score for liver transplantation". Liver Transpl. vol. 11. 2005. pp. 441-8.

(This work shows data that may allow the clinician to predict at the time of WD diagnosis which patients might respond to medicational therapy and which patients most likely will need a liver transplant. This is important because it directly relates to the patient's prognosis and the timing of possible liver transplantation.)

Roberts, EA, Schilsky, M. " AASLD Practice Guidelines Diagnosis and treatment of Wilson disease: an update". Hepatology. vol. 47. 2008. pp. 2089-2111.

(Readers are encouraged to review the practice guidelines adopted by the American Association for the Study of Liver Diseases after extensive expert peer review.)

Wong, RJ, Gish, R, Schilsky, S. "A clinical assessment of Wilson disease in patients with concurrent liver disease". J Clin Gastroenterol. vol. 45. 2011. pp. 267-73.

(This article underscores the importance of recognizing that accelerated liver injury occurs in those with WD having other liver diseases, particularly hepatitis C and hemochromatosis. A WD diagnosis should be considered especially in patients with other liver disease who are not responding to therapy.)

Korman, JD, Volenberg, I, Balko, J. " Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests". Hepatology. vol. 48. 2008. pp. 1167-74.

(In the acute liver failure setting, rapid diagnosis of WD is important. Standard workup results such as 24-hr urine copper and liver biopsy copper quantification usually are not immediately available. In this work, the authors propose that laboratory tests such as complete blood cell count, AST, ALT, bilirubin, and alkaline phosphatase (+/-serum copper) can be used to make a rapid diagnosis with close to 100% diagnostic accuracy.)

Shanmugiah, A, Sinha, S, Taly, AB. " Psychiatric manifestations in Wilson’s disease: a cross-sectional analysis". J Neuropsychiatry Clin Neurosci. vol. 20. 2008. pp. 81-5.

(Psychiatric disease in WD patients is an under recognized entity. This article alerts the clinician that up to two-thirds of WD patients may have concurrent psychiatric diagnoses. Identifying subtle behavioral signs and school performance changes in younger patients may aid in the diagnosis and decrease comorbidity.)

Akil, M, Brewer, GJ. " Psychiatric and behavioral abnormalities in Wilson’s disease". Adv Neurol. vol. 65. 1995. pp. 171-8.

Arnon, R, Annunziato, R, Schilsky, M. " Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults". Clin Transplant. vol. 25. 2011. pp. E52-E60.

(The authors report outcome results derived from data from a national transplant database, the United Network for Organ Sharing (UNOS). This analysis represents the largest number of pediatric and adult patients requiring liver transplant.)

Schumacher, G, Platz, KP, Mueller, AR. " Liver transplantation in neurologic Wilson’s disease". Transplant Proc. vol. 33. 2001. pp. 1518-9.

Sen, S, Felldin, M, Steiner, C. " Albumin dialysis and molecular adsorbents recirculating system (MARS) for acute Wilson's disease". Liver Transpl. vol. 8. 2002. pp. 962-7.

**The original authors for this chapter were Michael Schilsky and Richard Rosencrantz. The chapter was revised by Dr. Bruce R. Bacon.

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