IS CERULOPLASMIN A GOLD ENOUGH STANDARD FOR COPPER OVERLOAD?

Victor Tseng, MDResident Journal Club

April 2014, AVAMC

2 mg/d

Enterocyte

Portal Circulati

on

HepatocyteATP7

B

Cp-(Cu2+)n

Peripheral Blood

Bile (Enterohepatic Ciculation)

Diminished Synthetic Capacity

Cirrhosis/ESLD Congenital

Aceruloplasminemia Chronic Hepatitis

Increased Elimination Nephrotic

Syndrome/Proteinuria Protein-Losing Enteropathy X-Linked Menkes

True Copper Deficiency TPN Gastric Bypass Divalent Chelation

(Penacillamine)

Hepatocellular Injury Acute on Chronic Hepatitis

Heterozygosity Attenuated Compound

Heterozygotes Asymptomatic Carriers

Hyperestrogenism HRT/C Pregnancy

Inflammation (Acute Phase Reactant)

Serum Ceruloplasmin is…Spuriously decreased when

there isSpuriously increased when

there is

WHICH OF THESE CRITERIA PROVIDES A DEFINITIVE

DIAGNOSIS? Liver biopsy with [Cu2+] > 50 µg/g in whole tissue homogenate Triad: neuro/ψ s/sx + serum Cp < 20 mg/dL + urinary Cu2+ > 100 µg/dTriad: KF rings + neuro/ψ s/sx + serum Cp < 20 mg/dL Liver biopsy with positive copper stain and characteristic histopathology Allele-specific genetic testingNone of the above

WHICH ONE IS A KAYSER-FLEISCHER RING?

CLINICAL QUESTIONS OF THE STUDY

QUESTION 1What was the rate of adherence to

AASLD guidelines for assaying serum ceruloplasmin as a screen of Wilson

Disease?

QUESTION 2 Under these screening practices, what

were the test characteristics?

5011

424 4599

8 416 0 4599

2178 (7)

1781 (1)

1064 (0)

≤ 40 41 - 55 ≥ 56

Cp < 20 mg/dL Cp ≥ 20 mg/dL

“Confirmed” New WD

12 Known WD

424

37 387

Cp < 20 mg/dL

“Confirmatory Testing”(UCu2+ or Liver Biopsy)

Workup Terminated(possibly other diagnosis made)

Can you see the problem?

mg/dL WD “Confirmed

”

WD Ruled Out

Total

Cp < 20 8 416 424

Cp ≥ 20 0 4599 4599

Total 8 5015 5023

CONFUSION MATRIX – ALL PATIENTS (5023)

TP

FN

FP

TN

DESCRIPTIVE STATISTICS – ALL PATIENTS Prevalence (Pre-Test) = 8/5023 = 0.16%

Se = TP/(TP + FN) = 8/(8 + 0) = 1.0 Sp = TN/(TN + FP) = 4599/(4599+ 416) = 0.917

PPV = TP/(TP + FP) = 8/424 = 0.019 NPV = TN/(TN + FN) = 4599/4599 = 1.0

LR+ = Se/(1 – Sp) = 1.0/(1 – 0.917) = 12 LR- = (1 – Se)/Sp = 0

NNDx = Total/TP = 5023/8 = 627

BAYSIAN NOMOGRAM – ALL PATIENTS

LR+ = 12

LR- = 0

STUDY LIMITATIONS Two major sources of bias are present here

Verification Bias: Gold standard confirmatory testing or chart review was not applied equally regardless of serum Cp result

Spectrum Bias: Serum Cp is known to vary with presentation of disease (e.g. fulminant hepatic failure vs hemolytic crisis vs asymtomatic transaminitis)

MORE STUDY LIMITATIONS

Ultimately, the paper was designed to explore an epiphenomenon related to testing practices.

The paper was not intended to assess the validity of a diagnostic test (serum Cp) or determine receiver-operative curves.

BOTTOM LINE A positive serum Cp test confers a change of probability of 0.16% to around 2%

Ignoring verification bias, a negative serum Cp appears to rule out Wilson’s (perfect sensitivity)

Testing according to AASLD age guidelines does not change the test performance much

Testing serum Cp does not change further workup or management in > 90% of cases.

IMPORTANT UNANSWERED QUESTIONS

QUESTION 3How good is the test when applied to

patients after exclusion of other causes of hepatic disease?

QUESTION 4How does the test fare in different

manifestations of Wilson’s Disease?

THE BIG QUESTION

Wilson’s Disease is rare. Do we really need screening tests for rare diseases?

Can you think of any rare and treatable diseases for which we implement generalized or targeted screening?