What is the diagnosis in 2 words?

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Which of the following conditions is associated with macrocytic anemia?

Chronic kidney disease
Elevated reticulocyte count
Liver disease

Below is a differential diagnosis for macrocytosis:

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Now let’s look at the patient’s CBC over time:

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The following were the patient’s reticulocyte counts:

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On the first slide it was indicated that the patient had no evidence of bleeding. That leaves hemolysis as the most likely cause.

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The following is a review of commonly ordered hemolytic markers. Note how closely they overlap with changes in liver disease:

In hemolysis, most of the bilirubin is indirect; in liver disease both direct and indirect bilirubin are typically elevated.

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The hemolytic markers in this patient are shown here:

These data are consistent with (more than one answer may apply):

Hemolysis alone
Would not explain the elevated direct bilirubin.
Liver disease alone
Hemolysis and liver disease together
The elevated AST:ALT ratio in liver disease suggests alcoholic liver disease.

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Below is a differential diagnosis for hemolysis:

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You were told on the first slide that the peripheral smear was unremarkable. That is very helpful in narrow our differential diagnosis of hemolytic anemia:

ConditionFindings on smear
(in addition to polychromatophilia)
Warm autoimmune hemolytic anemiaSpherocytes
Cold autoimmune hemolytic anemiaRBC agglutination
Non-immune mediated
Hereditary spherocytosisSpherocytes
Hereditary elliptocytosis Elliptocytes
G6PD deficiencyNormal or with bite cells
PK deficiencySpiculated RBCs resembling spur cells, nRBC
SCDSickle cells, Howell-Jolly bodies, nRBC
TTP and other TMASchistocytes
DICNormal or with occasional schistocytes
Valve hemolysisSchistocytes
Cirrhosis with spur cell anemiaSpur cells (acanthocytes)
Zieve syndromeNormal or with stomatocytes, target cells
Wilson diseaseNormal
Clostridium perfringensMicrospherocytes
Babesiosis/malariaRBC inclusions

Note that a normal smear in the setting of hemolysis is most consistent with:

  • G6PD deficiency
  • PNH
  • Wilson disease
  • Zieve syndrome

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So far, we have a 28 yo M, previously well, presenting with fatigue and jaundice, found to have a hyperproliferative macrocytic anemia, shorted RBC survival consistent with hemolysis, hemolytic markers consistent with both hemolysis and liver disease, and a normal blood smear. Of the diagnoses most consistent with hemolysis + normal peripheral smear (see last slide), only Wilson disease and Zieve syndrome are associated with significant liver disease. It was stated in the initial presentation that that the patient was previously well, which makes Zieve syndrome less likely (as does the extent of liver failure). Indeed, the patient was diagnosed with Wilson disease!

Note that we have approached this case from a hematological angle (for teaching purposes). Of course, when the patient was admitted, he was assessed by the liver service (and hematology, among other services, was consulted). The liver team would have used a diagnostic scoring system (e.g., the Leipzig score) to secure the diagnosis. The Leipzig score includes the following parameter:

Patient results:

KF ringsPresent2
Neurological Normal0
Serum ceruloplasmin4 mg/dL2
Coombs negative HAPresent1
Liver copper347 mcg/g2
Urinary copper5093 mcg2
Mutation analysisNot done0

Easily meets the criteria for diagnosis of Wilson disease.

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