Diagnosis and management of Wilson’s disease

Richa ShuklaFaculty 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 1995 - ↓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 RAGen: NAD, lethargic but arousable to painful stimuliHEENT: icteric sclera, PERRL, EOMI, MMM, OP clearCV: tachycardic, no m/r/gChest: clear to auscultation bilaterallyAbd: soft, NT/ND, +BSExt: WWP, no clubbing or cyanosis, no LE edemaNeuro: oriented x1 (oriented to self), tremulous

Labs on admission

MCV 86.7

143

4.4 14

11

1.4472 9.4

29.6

10.291

INR 3.3Serum copper 56 µg/dL24 hour urine copper: 119 µg/LUrine Cu/Cr ratio 744 µg/g creatinineAnti-SMA normalAMA normalANA normal

Total bilirubin 13.4Direct bilirubin 7.0AST 323ALT 129Alk Phos 200Total protein 5.9 Albumin 1.4

114

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 15-35 years of age• Children present with liver disease, adults

with neurologic diseaseWilson, S Brain 34:295–509. 1912

Lorincz. Annals of the New York Academy of Sciences. January 2010Hilal 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 2014AASLD 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;27:358-362.

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

• 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!