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Victor Tseng, MD

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….

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Victor Tseng, MD

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  1. IS CERULOPLASMIN A GOLD ENOUGH STANDARD FOR COPPER OVERLOAD? Victor Tseng, MD Resident Journal Club April 2014, AVAMC

  2. Bile (EnterohepaticCiculation) Enterocyte Hepatocyte 2 mg/d ATP7B Portal Circulation Cp-(Cu2+)n Peripheral Blood

  3. Serum Ceruloplasmin is… Spuriously decreased when there is Spuriously increased when there is • Diminished Synthetic Capacity • Cirrhosis/ESLD • Congenital Aceruloplasminemia • Chronic Hepatitis • Increased Elimination • NephroticSyndrome/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)

  4. 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/d • Triad: KF rings + neuro/ψ s/sx + serum Cp < 20 mg/dL • Liver biopsy with positive copper stain and characteristic histopathology • Allele-specific genetic testing • None of the above

  5. WHICH ONE IS A KAYSER-FLEISCHER RING?

  6. CLINICAL QUESTIONS OF THE STUDY QUESTION 1 What 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?

  7. ≤ 40 41 - 55 ≥ 56 2178 (7) 1781 (1) 1064 (0) 5011 12 Known WD Cp < 20 mg/dL Cp ≥ 20 mg/dL 424 4599 8 416 0 4599 “Confirmed” New WD

  8. Cp < 20 mg/dL 424 37 387 “Confirmatory Testing” (UCu2+ or Liver Biopsy) Workup Terminated (possibly other diagnosis made) Can you see the problem?

  9. CONFUSION MATRIX – ALL PATIENTS (5023) TP FP FN TN

  10. 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

  11. BAYSIAN NOMOGRAM – ALL PATIENTS LR+ = 12 LR- = 0

  12. 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 vsasymtomatictransaminitis)

  13. MORE STUDY LIMITATIONS • Ultimately, the paper was designed to explore an epiphenomenon related to testing practices. • The paper was notintended to assess the validity of a diagnostic test (serum Cp) or determine receiver-operative curves.

  14. BOTTOM LINE • A positive serum Cp test confers a change of probability of 0.16% to around 2% • Ignoring verification bias, anegative 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.

  15. IMPORTANT UNANSWERED QUESTIONS QUESTION 3 How good is the test when applied to patients after exclusion of other causes of hepatic disease? QUESTION 4 How does the test fare in different manifestations of Wilson’s Disease?

  16. 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?

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