Wilson DiseaseClinical Epidemiology of Patients With Concurrent Liver Disease

Robert Wong, M.D.CPMC Wilson Disease Symposium

5/2/2009

No financial disclosures

Objectives● Brief overview of general epidemiology and

clinical presentation● Current available diagnostic tools● Leipzig criteria: improving clinical diagnosis● Understand the different clinical epidemiology of

Wilson disease in patients with concurrent liver disease

Background

● Wilson Disease is a rare autosomal recessive disorder of impaired copper secretion

● Worldwide prevalence of 30 per million population

● Usually a disease of children and young adults with most cases identified within the first 4 decades of life

● More than 300 known mutations of Wilson disease gene, but complicated by unclear consequences of variable penetrance and compound heterozygosity

Clinical Presentation

● Hepatopathy: spectrum of clinical findings

– Subclinical asymptomatic elevation in liver enzymes

– Mild histopathological evidence of steatosis

– Fulminant hepatic failure or end stage liver disease● Neurological manifestations: motor pathology

– Parkinsonism (akinesia and rigidity)

– Pseudosclerotic (tremor and dysarthria)

– Dystonia

– Chorea● Kayser Fleischer rings

Diagnostic Evaluation● Clinical suspicion● Ceruloplasmin● 24 hour urinary copper excretion● Urinary copper excretion with pencillamine

challenge● Quantitative hepatic copper concentration via

liver biopsy● Mutation analysis

Leipzig Criteria

● 8th International Meeting on Wilson disease and Menkes disease, European Association for the Study of the Liver (April 2002)

● 8 item scoring system for diagnosis of WD● KF rings; typical neuropsychiatric manifestations;

hemolytic anemia, 24 hour urniary excretion, hepatic copper concentration, histologic copper staining, ceruloplasmin, mutation analysis

WD and Concomitant Liver Disease

● Rarity of WD has led to few large scale studies to investigate clinical epidemiology

● In particular, WD in patients with concurrent liver diseases have not been fully studied

● Concurrent liver diseases– Novel: few case reports of Wilson patients with coexisting

liver diseases

– May complicate and potentially delay diagnosis of WD

– Synergistic relationship leading to more progressive liver damage

Methods

● Retrospective cohort study (1999-2008) among our community-based health care system that includes facilities in northern CA and Nevada

● Review of electronic data (OTTR) and paper charts

● Majority of patients diagnosed with hepatic copper >250 mcg/g dry liver wt

● Some cases were diagnosed based on clinical sx, other supporting biochemical data, and with revised cutoff >65mcg/g dry liver wt per expert consultation

● Retrospective evaluation of Leipzig criteria

Results

● 43 total patients with Wilson Disease identified● Ten patients had concurrent liver disease of

another etiology at presentation● Overall average age at diagnosis: 31.9 years● Patients with concurrent liver disease diagnosed

at significantly older ages (47.2 y vs 26.8 y, p<0.001)

Unpublished data

Patient Demographics

WD Only (N=33) WD + Concurrent Liver Disease (N=10)

Age at diagnosisMean, (95% CI) 26.8 (N=30) (22.8-30.8) 47.2 (N=10) (37.9-56.5) p<0.00110-19 years 8 24.2% 0 0.0%20-29 years 13 39.4% 2 20.0%30-39 years 4 12.1% 1 10.0%40-49 years 2 6.1% 2 20.0%50+ years 3 9.1% 5 50.0%Unknown 3 9.1% 0 0.0%

Kayser-Fleischer ringsPresent 14 42.4% 1 10.0%

MortalityConfirmed deaths 4 (N=29) 13.8% 4 (N=8) 50.0%Lost to follow up 4 2

Concurrent Liver Disease Among Patient's with Wilson Disease

No concurrent liver diseaseHepatitis BHepatitis CHepatitis C and HCCHCC without Viral HepatitisAutoimmune liver diseaseHemochromatosis

78.7%, N=33

2.1%, N=1

4.2%, N=2

2.1%, N=1

2.1%, N=1

8.5%, N=4

2.1%, N=1

Distribution of Concomitant Liver Disease

– While depression was the most common concurrent neuropsychiatric manifestation, no significant differences in symptom distribution existed between the two groups

– A detailed comparison of biochemical data (chemistries, liver enzymes, and liver function tests) showed no statistically significant differences

– Serum copper and 24 hour urinary copper excretion values were not significantly different between the two groups

– Serum levels of ceruloplasmin were lower among patients with Wilson disease only (17.0 mg/dL, 95% CI, 10.6-23.4) compared to patients with Wilson disease and concomitant liver disease (28.6 mg/dL, 95% CI, 21.0-36.2), p=0.02

Clinical and Biochemical Comparisons

Histopathological Comparisons

Unpublished data

WD only (N=33) WD + concurrent liver disease (N=10)

Liver biopsy resultsEvidence of cirrhosis 15 45.5% 10 100.0%

Quantitative copper concentrationMean, 95% CI 625.2 (N=20) (438.3-812.1) 651.7 (N=9) (209.7-1093.7) >250 mcg/g dry wt 15 75.0% 6 66.7% 75-250 mcg/g dry wt 5 25.0% 3 33.3%

Liver transplant 11 33.3% 1 10.0%

0.00

0.25

0.50

0.75

1.00

Ove

rall

Sur

viva

l Pro

babl

ity

10 0 0 0 0 0GROUP = 230 11 7 3 1 0GROUP = 1

Number at risk

0 10 20 30 40 50Time (years)

GROUP = 1 GROUP = 2

Kaplan-Meier Survival Functions

P = 0.0292 by log rank test

Kaplan-Meier survival curves for Wilson disease patients with versus without concurrent liver disease.Group 1 = no concurrent liver disease, Group 2 = concurrent liver disease.Unpublished data

No Concurrent Liver Disease Concurrent Liver Disease

Score 4 or more 24 92.3% 4 44.4%Score 2-3 2 7.7% 5 55.6%Score 0-1 0 0.0% 0 0.0%Score Unknown 7 - 1 -

4 or more: diagnosis of Wilson disease highly likely2-3: diagnosis of Wilson disease probable, more investigations indicated0-1: diagnosis of Wilson disease unlikely

A comparison of Leipzig scores among Wilson disease patients with and without concurrent liver disease

Leipzig Scores in Wilson Disease Patients

Unpublished data

Conclusions

● Wilson disease is a rare familial disease of copper secretion, which if left untreated results in progressive liver damage and death

● Wilson disease in patients with concomitant liver disease– Diagnosed at significantly older ages– More evidence of severe liver disease– Lower rates of liver transplantation– Significantly greater mortality

Conclusions

– Concurrent liver disease may delay diagnosis and treatment of Wilson disease allowing progressive liver damage

– Synergistic relationship between Wilson disease and underlying liver pathology may result in more aggressive natural history of illness

– Lower rates of liver transplantation and higher overall mortality may reflect the diagnosis of Wilson disease at later stages with more severe pathology

– Patients with Wilson disease and concurrent liver disease of another pathology pose a complex diagnostic and clinical challenge

Future Directions

● More studies needed to investigate the clinical and pathological relationship between Wilson Disease and other forms of liver disease

● Evaluation of more recent advances in diagnostic guidelines for Wilson's

● Efficacy of mutation analysis by whole-genome sequencing

References1. Roberts EA and Schilsky MI. Diagnosis and treatment of Wilson's disease: An update. Hepatology 2008;47:2089-2111.2. Berman DH, Leventhal RI, Gavaler JS, et al. Clinical differentiation of fulminant Wilsonian hepatitis from other causes of hepatic failure. Gastroenterol 1991;100:1129-34.3. Steindl P, Ferenci P, Dienes HP, et al. Wilson's disease in patients presenting with liver disease: A diagnostic challenge. Gastroenterol 1997;113:212-8.4. Milkiewicz P, Saksena S, Hubscher SG, et al. Wilson's disease with superimposed autoimmune features: Report of two cases and review. J Gastroenterol Hepatol 2000;15:570-45. Lembowicz K, Kryczka W, Walewska-Zielecka B, et al. Wilson's disease coexisting with viral hepatitis type C: A case report with histological and ultrastructural studies of the liver. Ultra Pathol 1999;23:39-446. Cauza E, Maier-Dobersberger T, Polli C, et al. Screening for Wilson's disease in patients with liver diseases by serum ceruloplasmin. J Hepatol 1997;27:358-62.7. Iwadate H, Ohira H, Suzuki T, et al. Hepatocellular carcinoma associated with Wilson's disease. Int Med 2004;43:1042-45 8. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver International 2003;23:139-142.