victor tseng, md
DESCRIPTION
IS CERULOPLASMIN A GOLD ENOUGH STANDARD FOR COPPER OVERLOAD?. Victor Tseng, MD. Resident Journal Club April 2014, AVAMC. Bile ( Enterohepatic Ciculation ). Enterocyte. Hepatocyte. 2 mg/d. ATP7B. Portal Circulation. Cp-(Cu 2+ ) n. Peripheral Blood. Serum Ceruloplasmin is…. - PowerPoint PPT PresentationTRANSCRIPT
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?