Diagnosis and management of Wilsons disease Richa Shukla

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 • 48 M with h/o Wilson’s disease diagnosed in 1995 - ↓ceruloplasmin, ↑ 24 hour 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 Social history -Denied Et. OH and drug use, former smoker Past surgical history -TIPS 7/2014 -R shoulder titanium implant 2008 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 O 2 100% 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 x 1 (oriented to self), tremulous

Labs on admission 143 114 11 4. 4 14 1. 44 72 9. 4 10. 2 91 29. 6 MCV 86. 7 Total bilirubin 13. 4 Direct bilirubin 7. 0 AST 323 ALT 129 Alk Phos 200 Total protein 5. 9 Albumin 1. 4 INR 3. 3 Serum copper 56 µg/d. L 24 hour urine copper: 119 µg/L Urine Cu/Cr ratio 744 µg/g creatinine Anti-SMA normal ANA normal

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 T 2 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 ATP 7 B gene on chromosome 13 • Defective biliary excretion of copper • 30 affected individuals per million population • Majority diagnosed 15 -35 years of age • Children present with liver disease, adults with neurologic disease Wilson, S Brain 34: 295– 509. 1912 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/24 h diagnostic – Penicillamine challenge • Serum copper – Non-ceruloplasmin bound copper – diagnostic test for Wilson’s – [Serum copper (µg/d. L)] – [3 * serum ceruloplasmin (mg/d. L)] – Variable, multiple confounding factors – Untreated WD: non-ceruloplasmin Cu levels > 25µg/d. L Dalvi et al. Disease Monthly September 2014 AASLD guidelines Wilson’s disease

Diagnosis • Serum ceruloplasmin – Level below 20 mg/d. L 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: 358 -362.

Use of ceruloplasmin • AASLD guidelines: – Extremely low serum ceruloplasmin level (<50 mg/L or <5 mg/d. L) 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 ATP 7 B 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 • 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: e 50

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/24 h (200– 500 μg/24 hour) • Maintenance phase (with zinc) – 24 hour urinary copper excretion <2. 0 μmol/24 h (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 : 44 M 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!