Diagnosis and management of Wilson’s disease Richa Shukla Faculty mentor: Dr. Pappas November 6, 2014

Case discussion Reason for consult: Liver transplant evaluation for cirrhosis due to Wilson’s disease

HPI 48M with h/o Wilson’s disease diagnosed in ↓ceruloplasmin, ↑24hour urine copper and K-F rings Treated with tetrathiomolybdate for 8 weeks in 1996, started on zinc acetate Liver biopsy results 7/20/1999 consistent with cirrhosis EGD 5/2009 and 6/2009 – non-bleeding varices

HPI 2011 – patient blacked out while driving, killing a motorcyclist. Was subsequently incarcerated Family reports irregular medical care during incarceration Released in 2/2014 – family noted decline in mental status Hospitalized x 2 for PSE and bleeding varices in 3/2014, 6/2014. Underwent TIPS 7/2014

HPI 9/17/14 – hospitalized at OSH for AMS, transferred to a tertiary care hospital. Mental status improved initially but subsequently patient refused lactulose and MS again decompensated Transferred to a Houston hospital for OLT evaluation

HPI Admitted to Houston hospital MICU due to obtundation Started on lactulose and rifaximin via NG tube Also started on zinc acetate and trientine

PMH Past medical history -Wilson’s disease -Rotator cuff injury Past surgical history -TIPS 7/2014 -R shoulder titanium implant 2008 Social history -Denied EtOH and drug use, former smoker Family history -Female cousin – Wilson’s disease -Male cousin – Wilson’s disease -Father – unknown cancer

Physical Exam T 98.2 BP 148/62 R 15 P 122 O2 100% on RA Gen: NAD, lethargic but arousable to painful stimuli HEENT: icteric sclera, PERRL, EOMI, MMM, OP clear CV: tachycardic, no m/r/g Chest: clear to auscultation bilaterally Abd: soft, NT/ND, +BS Ext: WWP, no clubbing or cyanosis, no LE edema Neuro: oriented x1 (oriented to self), tremulous

Labs on admission MCV INR 3.3 Serum copper 56 µg/dL 24 hour urine copper: 119 µg/L Urine Cu/Cr ratio 744 µg/g creatinine Anti-SMA normal AMA normal ANA normal Total bilirubin 13.4 Direct bilirubin 7.0 AST 323 ALT 129 Alk Phos 200 Total protein 5.9 Albumin

Imaging results RUQ US 10/2/14 – Heterogenous and nodular liver consistent with cirrhosis. Gallstones, contracted gallbladder. No definite evidence of acute cholecystitis MRI Brain 10/4/14 – Mildly increased restricted diffusion and T2 signal within the R caudate and thalamus. Also other foci of increased signal scattered within the white matter.

Other results EEG 9/30/14 – Abnormal study due to moderate diffuse slowing of the background rhythms. No evidence for epileptiform activity.

Clinical Questions How is Wilson’s disease diagnosed? What treatment options are available for Wilson’s disease? What is the role of liver transplantation in Wilson’s disease?

Clinical Questions How is Wilson’s disease diagnosed? What treatment options are available for Wilson’s disease? What is the role of liver transplantation in Wilson’s disease?

Background First written about in 1912 by Kinnier-Wilson Autosomal recessive disease – mutation of ATP7B gene on chromosome 13 Defective biliary excretion of copper 30 affected individuals per million population Majority diagnosed years of age Children present with liver disease, adults with neurologic disease Wilson, S Brain 34:295– Lorincz. Annals of the New York Academy of Sciences. January 2010 Hilal Case Reports in Medicine September 2014 AASLD Criteria Diagnosis and Treatment of Wilson’s Disease: an update

Clinical presentation Neurologic manifestations – 98% have Kayser-Fleischer rings – Classification: dysarthric, dystonic, tremulous, pseudosclerotic or parkinsonian – Chorea, dementia, seizures, hyperreflexia, autonomic dysfunction, risus sardonicus Psychiatric symptoms – Earlier presentation – Depression most common

Kayser-Fleischer rings

Clinical presentation Hepatic manifestations – Range from asymptomatic disease to acute liver failure – Younger patients develop acute hepatitis with ↑AST, jaundice, abdominal pain – Acute liver failure – Coomb’s negative hemolytic anemia, low uric acid, normal/low-normal alkaline phosphatase, coagulopathy, renal failure

Diagnosis Classic Wilson’s disease: Age 5-40, decreased ceruloplasmin, Kayser-Fleischer rings High index of clinical suspicion, multisystem symptomatology Family screening of first-degree relatives must be undertaken Ala et al. Lancet February 2007

Adapted from AASLD guidelines for management of Wilson’s disease

Diagnosis 24 hour urine copper excretion – Concentration > 100 µg/24h diagnostic – Penicillamine challenge Serum copper – Non-ceruloplasmin bound copper – diagnostic test for Wilson’s – [Serum copper (µg/dL)] – [3 * serum ceruloplasmin (mg/dL)] – Variable, multiple confounding factors – Untreated WD: non-ceruloplasmin Cu levels > 25µg/dL Dalvi et al. Disease Monthly September 2014 AASLD guidelines Wilson’s disease

Diagnosis Serum ceruloplasmin – Level below 20 mg/dL SUGGESTIVE – Low levels seen: 1% normal population, 10% of heterozygous carriers for WD, Menke’s disease, nephrotic syndrome – Normal ceruloplasmin seen in 20% WD patients Cauza et al. –PPV of low ceruloplasmin 5.9% Cauza et al. J Hepatol 1997;27:

Use of ceruloplasmin AASLD guidelines: – Extremely low serum ceruloplasmin level (<50 mg/L or <5 mg/dL) should be taken as strong evidence for the diagnosis of WD. – Modestly subnormal levels suggest further evaluation is necessary. – Serum ceruloplasmin within the normal range does not exclude the diagnosis

Other diagnostic tests Hepatic copper concentration - > 250 µg/g dry weight Kayser-Fleischer rings – slit-lamp exam – Most patients with neuropsychiatric symptoms will show KF rings – 50–60% of patients with hepatic WD

Genetic testing 25% probability that sibling of affected patient has WD Genetic testing – standard of screening in family members Direct sequencing of ATP7B for disease specific mutations – standard for molecular diagnosis Finding of two mutations or homozygosity for one mutation highly suggestive of WD Schilsky et al Curr Gastroenterol Rep (2010) 12:57–61

Genetic mutations

Liver biopsy – Mild steatosis (micro- and macro-vesicular) – Glycogenated nuclei in hepatocytes – Focal hepatocellular necrosis – Features of AIH – Fibrosis, macronodular cirrhosis – Early stages Cu in cytoplasm, later stages in lysosomes

Liver biopsy

Imaging - MRI Shivakumar R, and Thomas S V Neurology 2009;72:e50

Diagnostic Index Dalvi et al. Disease A Month Sept 2014

Clinical Questions How is Wilson’s disease diagnosed? What treatment options are available for Wilson’s disease? What is the role of liver transplantation in Wilson’s disease?

Treatment Goal of treatment – Removal of copper from various organs – Symptomatic control

Treatment - chelation Pencillamine – First oral agent to treat WD – Side effects: neurologic deterioration, bone marrow suppression, hypersensitivity, lupus-like syndrome Trientine – Promotes urinary excretion of copper – Fewer side effects than penicillamine – Combine with zinc for maintenance therapy

Treatment - chelation Zinc – Sequesters copper within enterocytes, also complexes copper in hepatocytes in non-toxic form – Used in pre-symptomatic, maintenance phase Ammonium tetrathiomolybdate – Complexes with dietary copper when given with meals – reducing absorption – Complexes with free copper and serum albumin when given between meals – excreted in bile

Monitoring treatment Initial chelation therapy – 24 hour urinary copper excretion of 3–8 μmol/24h (200–500 μg/24 hour) Maintenance phase (with zinc) – 24 hour urinary copper excretion <2.0 μmol/24h (125 μg/24 h) Non-ceruloplasmin copper: 50–150 μg/L AASLD guidelines, Wilson’s disease

Clinical Questions How is Wilson’s disease diagnosed? What treatment options are available for Wilson’s disease? What is the role of liver transplantation in Wilson’s disease?

Role for liver transplantation Acute liver failure Decompensated liver disease unresponsive to medical therapy One-year survival following liver transplantation 79%-87% Eghtesad et al. Liver Transplant Surgery November 2009

Long-term outcomes in WD Beinhardt et al. – retrospective cohort study of 229 patients between 1961-April 2013 Long term treatment outcomes studied in 162 patients, average follow-up of 14.8 ± 11.4 yrs 26% fully recovered, 24% improved, 25% stable 13% of patients required OLT during study period Overall shows long-term favorable outcomes in WD patients receiving regular care Beinhardt et al. CGH April 2014

OLT in neurologic disease Stracciari et al : 44M with WD, cirrhosis and neurologic manifestations – post OLT showed improvement in motor function, disappearance of K-F rings, normalization of copper balance, reversal of MRI abnormalities Stracciari et al. JAMA Neurology March 2000

OLT in neurologic disease Guarino et al – presented case of rapid deterioration in neurological function after OLT in patient with hepatic and neurologic involvement – basal ganglia damage is irreversible – early post-operative central pontine and extrapontine myelinolysis Guarino et al. Acta Neurologica Scandinavica November 1995

Summary Diagnosis – serum ceruloplasmin, 24 hour urine copper, K-F rings, liver biopsy, imaging Treatment – chelation agents (D-penicillamine v. trientine), symptomatic treatment Liver transplantation for ALF, refractory disease Unclear benefits and possible harm of OLT in neurologic disease With chelation therapy and OLT, prolonged survival has become the norm

Thank you!