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Macro–Aspartate Transaminasemia: The Macroenzyme Phenomenon as a Diagnostic Dilemma

      To the Editor: Macroenzymes are normal enzymes or isoenzymes that have been complexed to an immunoglobulin, frequently of the IgG or IgA class.
      • Litin SC
      • O'Brien JF
      • Pructt S
      cl al. Macroenzyme as a cause of unexplained elevation of asparlate aminotransferase.
      • Klonoff DC
      Macroamylasemia and oilier immunoglobulin-com-plexed enzyme disorders.
      • Remaley AT
      • Wilding P
      Macroenzymes: biochemical characterization, clinical significance, and laboratory detection.
      • Miftlin TE
      • Bruns DE
      • Wrotnoski U
      • et al.
      Macroamylase, macro crea-tine ki nase, and other macroenzymes.
      They have a higher molecular mass than the corresponding enzyme normally found in serum under either physiologic or pathophysiologic conditions.
      • Litin SC
      • O'Brien JF
      • Pructt S
      cl al. Macroenzyme as a cause of unexplained elevation of asparlate aminotransferase.
      Macroenzymes could also result from physicochemical binding to nonimmunoglobulin molecules found in the serum (such as hydroxyethyl starch from intravenous fluids) and lipid aggregates and complexing with α2-macroglobulins.
      • Remaley AT
      • Wilding P
      Macroenzymes: biochemical characterization, clinical significance, and laboratory detection.
      Although it remains uncertain whether macroenzymes cause disease or require treatment,
      • Remaley AT
      • Wilding P
      Macroenzymes: biochemical characterization, clinical significance, and laboratory detection.
      they can cause increased enzyme levels in the absence of disease. For example, macroamylasemia mimics pancreatic disease. Other macroenzymes that have been described are macro–creatine phosphokinase, macro–alkaline phosphatase, macro–aspartate aminotransferase (AST), macro–γ-glutamyltransferase (GGT), macro–lactate dehydrogenase (LDH), and rnacrolipase.
      • Remaley AT
      • Wilding P
      Macroenzymes: biochemical characterization, clinical significance, and laboratory detection.
      • Miftlin TE
      • Bruns DE
      • Wrotnoski U
      • et al.
      Macroamylase, macro crea-tine ki nase, and other macroenzymes.
      Report of a Case.—We describe a 70-year-old man with a history of depression. For more than 7 years he had been treated by several physicians for an isolated AST elevation that was detected on a routine blood chemistry panel. In 1996, the alanine aminotransferase (ALT) level was 28 U/L; AST, 455 U/L; GGT, 33 U/L; and alkaline phosphatase, 73 U/L. The peak serum AST level was 479 U/L in May 1997. He was otherwise asymptomatic. All other liver function test values, including repeated ALT, GGT, alkaline phosphatase, LDH, albumin and globulin, prothrombin time, and bilirubin measurements, had remained normal. Results of a hepatitis screen for viral hepatitides were negative. He was not taking any medications known to increase liver enzyme levels. In September 1998, he reported that he drank up to 2 or 3 beers a day, and his AST level was 436 U/L; he was advised to abstain from alcohol. Following abstinence from alcohol, the AST level decreased to between 250 and 272 U/L but no lower. In March 2000, the differential diagnosis of macro–aspartate transaminasemia (macro-AST) was considered for the first time. A diagnostic test, serum AST enzyme electrophoresis, was ordered. Macro-AST, accounting for nearly 100% of total serum AST, was evident on the enzyme electrophoresis carried out at Mayo Medical Laboratories. We have concluded that our patient, who remains asymptomatic despite the persistently elevated AST levels, needs no further work-up or treatment. Indeed, at a point during previous follow-up for the elevated AST, he was nearly subjected to a liver biopsy.
      Discussion.— The frequency of these macroenzyme phenomena remains uncertain. Based on data from 7 previous publications, the calculated frequency of macroamylasemia is 0.98% of subjects with normal amylase levels and 2.56% of subjects with hyperamylasemia.
      • Klonoff DC
      Macroamylasemia and oilier immunoglobulin-com-plexed enzyme disorders.
      The frequency of immunoglobulin-complexed LDH has been estimated at less than 1 in 10,000 population.
      • Biewenga J
      Serum laetate dehydrogenase isoertzymes linked to im-munoglobulin A.
      Several laboratory detection methods that measure different physical and chemical characteristics of macroenzymes compared with free enzymes are available. These methods include protein electrophoresis, differential precipitation with polyethylene glycol, measurements of heat stability, energy of activation, and solubility in solutions of ammonium sulfate. Advanced testing in inconclusive cases may require more complicated tests, including molecular mass estimation by gel filtration chromatography. Other options include immunoelectrophoresis, immunofixation, use of antibodies to the apoprotein moiety of lipoprotein carriers, and counterimmunoelectrophoresis.
      • Remaley AT
      • Wilding P
      Macroenzymes: biochemical characterization, clinical significance, and laboratory detection.
      • Miftlin TE
      • Bruns DE
      • Wrotnoski U
      • et al.
      Macroamylase, macro crea-tine ki nase, and other macroenzymes.
      We remind physicians to be aware of the asymptomatic macroenzyme phenomenon in the absence of a disease state. Prior documentation of a macroenzyme state in a patient should be given the same prominence in a patient's medical record as drug allergies. This way, invasive, costly, or even potentially lifethreatening investigations or treatment may be averted.

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        • O'Brien JF
        • Pructt S
        cl al. Macroenzyme as a cause of unexplained elevation of asparlate aminotransferase.
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        • Klonoff DC
        Macroamylasemia and oilier immunoglobulin-com-plexed enzyme disorders.
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        • Wilding P
        Macroenzymes: biochemical characterization, clinical significance, and laboratory detection.
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        • Wrotnoski U
        • et al.
        Macroamylase, macro crea-tine ki nase, and other macroenzymes.
        Clin Chem. 1985; 31: 1743-1748
        • Biewenga J
        Serum laetate dehydrogenase isoertzymes linked to im-munoglobulin A.
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