Lactate Dehydrogenase (LD) Isoenzymes
Lactate Dehydrogenase (LD) IsoenzymesUpdated June 14 2007
    
Number
001842
CPTCPT - Updated July 18 2007
83625; 83615
SynonymsSynonyms - Updated November 19 2007
Lactic Acid Dehydrogenase Isoenzymes ; LDH Isoenzymes ; LD Isoenzymes
Test IncludesTest Includes - Updated November 19 2007
Total serum LD and relative percentage of isoenzymes (LD1-5)
Specimen
Serum
Volume
3 mL
Minimum Volume
1 mL
Container
Red-top tube
Collection
Separate serum from cells within 45 minutes of collection.
Storage InstructionsStorage Instructions - Updated November 19 2007
Maintain specimen at room temperature. Do not refrigerate or freeze. LD5 is least stable with 13% lost at room temperature after 48 hours, 18% lost at refrigerated temperatures.
Patient Preparation
Cardiac enzymes and isoenzymes are best interpreted as a sequential series. Typically, a series of 3: 1 at admission (or initial event) and 2 more at 6- to 8-hour intervals.
Causes for Rejection
Hemolysis; prolonged contact of serum with red cells; specimen received frozen; specimen older than 48 hours after collection at time of testing
Reference IntervalReference Interval - Updated November 19 2007
Total: 100-250 IU/L; LD1: 16% to 35%; LD2: 24% to 41%; LD3: 16% to 27%; LD4: 5% to 14%; LD5: 5% to 24%. See table.
LD Isoenzyme Interpretation

Abbrev1 Total LDH LD1 LD2 LD3 LD4 LD5
Case 1HHH- --
Case 2HHH- --
Case 3HH>H- --
Case 4HH>H- -H
Case 5HHH- -H
Case 6H--- HH
Case 7H-HH H-
Case 8HHHH HH
Case 9H--- --
Case 10N--- --
Case 11H--- -H
Case 12 Other patterns not shown

1See following interpretation of abbreviations
H = high (increased)
- = within reference (normal) interval or decreased
N = within reference (normal) interval

Interpretations:

Case 1: Patient specimen was visibly hemolyzed which may have produced the elevations of LD1 and LD2 on the LD isoenzyme pattern.

Case 2: The LD isoenzyme pattern demonstrates elevations of LD1and LD2. These increases would be compatible with diagnostic considerations involving myocardial infarction, megaloblastic anemia, acute renal infarction, in vivo hemolytic process (eg, hemolytic anemia), or in the later stages of muscular dystrophy.

Case 3: The LD isoenzyme pattern demonstrates LD1 greater than LD2. In the appropriate clinical setting, this pattern is most compatible with postmyocardial infarction occurring at least 8-12 hours prior to venipuncture.

Case 4: The LD isoenzyme pattern demonstrates LD1greater than LD2 and an increase of LD5. This pattern would be most compatible with passive hepatic congestion following an acute myocardial infarction or right-sided congestive heart failure associated with myocardial infarction.

Case 5: The LD isoenzyme pattern demonstrates elevations of LD1 and LD2and an increase of LD5. This pattern would be compatible with diagnostic considerations involving passive hepatic congestion or right-sided congestive heart failure which may have followed acute myocardial damage.

Case 6: The LD isoenzyme pattern demonstrates elevations of LD4and LD5. These increases would be compatible with hepatic (cirrhosis, viral hepatitis, toxic hepatitis) or skeletal muscle injury. This pattern may also be associated with congestive heart failure.

Case 7: The LD isoenzyme pattern demonstrates elevations of LD2, LD3 and LD4. Increases of these isoenzyme fractions are nonspecific but have been associated with septic shock, pulmonary emboli, and some neoplastic processes.

Case 8: The LD isoenzyme pattern demonstrates elevations of all isoenzymes without dominating fractions. This pattern is nonspecific but has been associated with septic shock, pulmonary emboli, and some neoplastic processes.

Case 9: The LD isoenzyme pattern appears normal despite elevation of the total LD.

Case 10: The LD isoenzyme pattern appears normal with a normal total LD.

Case 11: The LD isoenzyme pattern demonstrates an elevated LD5 fraction which may be associated with hepatic anoxia due to congestive heart failure or the early stages of muscular dystrophy.

Case 12: The LD isoenzyme pattern is nonspecific. Recommend correlation with the clinical condition of the patient.

UseUse - Updated November 20 2007
Changes of LD isoenzymes periodically measured following onset of chest pain, studying the relationships of the anodic fractions, provide important information for the differential diagnosis of acute infarct of myocardium. The differential diagnosis of certain other diseases is enhanced as well with use of LD isoenzymes.

Useful in the differential diagnosis of acute myocardial infarction, megaloblastic anemia (folate deficiency, pernicious anemia), hemolytic anemia, and very occasionally renal infarct. These entities are characterized by LD1 increases, often with LD1: LD2 inversion.

The isomorphic pattern (total LD significantly high with no increase in percentage, of any fraction) is seen with neoplasia, cardiorespiratory diseases, hypothyroidism, infectious mononucleosis, and other inflammatory states, uremia, and necrosis.

LD5 increases are seen with striated muscle lesions (eg, trauma) and with liver diseases (eg, hepatic congestion, congestive heart failure, hepatitis, cirrhosis, alcoholism). LD5 increase is probably more significant when the LD5: LD4 ratio is increased.

Although a modicum of controversy exists regarding the most suitable criteria for LD isoenzymes for the diagnosis of acute myocardial infarction, almost all laboratories recognize abnormality when LD1 equals or is greater than LD2. Alternatives to LD1 greater than LD2 have been proposed. Using an electrophoretic method (Helena), Rotenberg et al suggested the criterion of LD1 >90 units/L.1 A 1988 study examines application of LD1: LD4 and other ratios and finds that the LD1: LD4 ratio optimizes earlier and is the most powerful diagnostic ratio for acute myocardial infarction.2

A few percent of normal individuals may have LD1: LD2 ratios as high as 0.81. A ratio of 0.82-0.99 is suspicious of myocardial injury. A ratio >1.0 is diagnostic of myocardial injury, if other clinical criteria are met. In unstable angina, an increase of the LD1: LD2 ratio is described with normal total LD.3 However, progressively increasing LD1: LD2 ratio without complete inversion may have diagnostic significance for acute myocardial infarct.4

Persistent LD1: LD2 flip following acute myocardial infarct may represent a marker for reinfarction.5 Especially when acute myocardial infarction is complicated by shock, the isomorphic pattern may be found.6 LD1: LD2 inversion commonly appears subsequent to the isomorphic pattern in instances of acute myocardial infarction.7

The appearance of a LD "flip" (when LD1 is greater than LD2) is extremely helpful in diagnosis of MI. The presence of a LD "flip" a day following or with the detection of CK-MB is essentially diagnostic of MI, if baseline cardiac enzymes/isoenzymes are normal and if rises and falls are as anticipated for the diagnosis of acute MI. While CK-MB peaks 12-24 hours after onset of infarction, LD isoenzymes usually become diagnostic at about 36-55 hours after onset and return to normal between 3 and 14 days after onset.

LimitationsLimitations - Updated November 19 2007
Timing is important in diagnosis of acute myocardial infarct (MI). In a small percentage of patients with acute myocardial infarction, the expected flip (reversal) of LD1: LD2 does not occur; in such patients, there is often simply an increase in LD1.
Methodology
Electrophoresis
Additional InformationAdditional Information - Updated November 19 2007
Patterns of LD isoenzymes in acute pulmonary edema include the isomorphic pattern and LD5 increase.8 Serum LD increases also in patients with bacterial pneumonia, in whom LD isoenzyme patterns are described.9

Macroenzymes, high molecular weight complexes, occur with LD as well as with CK and other enzymes. LD isoenzymes may complex to IgA or IgG. Such LD macroenzymes are characterized by abnormal position of isoenzyme bands, broadening or abnormal motility of a band and otherwise unexplained increase of total serum LD. Some of these patients have abnormal ANA results and IgG complexes.10 Some have abnormalities of light chains.11 Treatment with streptokinase was found to produce a LD-streptokinase complex which was seen as a band at the origin in electrophoresis.12

An isoenzyme band cathodal to LD5 has been called LD6. It is not an immunoglobulin complex. It has occurred in subjects with liver disease and is said to indicate a grave prognosis.10,13,14

The association between LD1 and testicular seminoma has been widely recognized. Its relationship to nonseminomatous testicular tumors as well are described.15 The ovarian equivalent of seminoma is dysgerminoma, which also may relate to LD1 increases.16,17 A variety of malignant tumors are characterized by total LD increases, sometimes with isomorphic patterns7 or with LD5 increases.18 Increase LD5: LD1 ratio is suggestive of prostatic carcinoma or other cancers.19 Increases in LD1: LD4 ratio was found to be a good indicator of MI.20

In a series of 220 patients with carcinoma of breast, LD was the most common enzyme elevated. The nonspecificity of single enzyme elevation was discussed, but enzymes provide an inexpensive baseline for postoperative follow-up. Enzyme elevation defines a subgroup of patients deserving further evaluation.21 In malignancy of various types, there is reported an abnormal isoenzyme of LD migrating between albumin and LD1 on agarose gel electrophoresis.22

An inverted LD5: LD4 ratio is not to be confused with LD1: LD2 ratio, used to evaluate acute MI. There is evidence that when LD5 sufficiently exceeds LD4, liver disease might exist. Such liver disease might be primary or secondary (eg, congestive heart failure). Additional tests which may be useful, if clinically indicated, to work up such possible liver disease or injury might include ALT (SGPT), GGT, serum protein electrophoresis, and prothrombin time. LD5 is the striated muscle as well as the liver fraction. Although striated muscle problems are usually clinically obvious, occasionally the physician does not get a clinical history of the postictal state or of various withdrawal syndromes. In such situations, a CK may be helpful.

FootnotesFootnotes - Updated August 7 2007
      1. Rotenberg Z, Davidson E, Weinberger I, et al. The efficiency of lactate dehydrogenase isoenzyme determination for the diagnosis of acute myocardial infarction. Arch Pathol Lab Med. 1988; 112(9):895-897.
      2. Loughlin JF, Krijnen PM, Jablonsky G, et al. Diagnostic efficiency of four lactate dehydrogenase isoenzyme-1 ratios in serum after myocardial infarction. Clin Chem. 1988;34:1960-1965.
      3. Rotenberg Z, Weinberger I, Sagle A, et al. Lactate dehydrogenase isoenzymes in serum during unstable angina. Clin Chem. 1986; 32:1566-1567.
      4. Jablonsky G, Leung FY, Henderson AR. Changes in LD1/LD2 ratio during the first day after myocardial infarction. Clin Chem. 1985; 31:1621-1624.
      5. Rotenberg Z, Weinberger I, Sagie A, et al. Lactate dehydrogenase isoenzymes in serum during recent acute myocardial infarction. Clin Chem. 1987; 33:1419-1420.
      6. Rotenberg Z, Weinberger I, Davidson E, et al. Atypical patterns of lactate dehydrogenase isoenzymes in acute myocardial infarction. Clin Chem. 1988; 349(6):1096-1098.
      7. Jacobs DS, Robinson RA, Clark GM, et al. Clinical significance of the isomorphic pattern of the isoenzymes of serum lactate dehydrogenase. Ann Clin Lab Sci. 1977;7:411-421.
      8. Rotenberg Z, Weinberger I, Davidson E, et al. Patterns of lactate dehydrogenase isoenzymes in serum of patients with acute pulmonary edema. Clin Chem. 1988; 34(8)1882-1884.
      9. Rotenberg Z, Weinberger I, Davidson E, et al.Significance of isolated increases in total lactate dehydrogenase and its isoenzymes in serum of patients with bacterial Pneumonia. Clin Chem. 1988; 34(7):1503-1505.
      10. Gorus F, Aelbrecht W, Van Camp B. Circulating IgG-complex, dissociable by addition of NAD+. Clin Chem. 1982;28:236-239.
      11. Pesce MA. The CK and LD macroenzymes. Lab Management.1984; 22:29-41.
      12. Podlasek SJ, Dufour DR, McPherson RA. Alterations lactate dehydrogenase isoenzyme patterns after therapy with streptokinase of streptococcal infection. Clin Chem.1989; 35(8):1763-1766.
      13. Vladutiu AO. Cathodic lactate dehydrogenase (LDH 6): A sign of ominous prognosis? Arch Pathol Lab Med. 1983;107:612-613.
      14. Wolf PL. Lactate dehydrogenase-6: A biochemical sign of serious hepatic circulatory disturbance. Arch Intern Med. 1985; 145:1396-1397.
      15. Von Eyben FE, Blaabjerg O, Petersen PH, et al. Serum lactate dehydrogenase isoenzyme 1 as a marker of testicular germ cell tumor. J Urol. 1988; 140(5):989-990.
      16. Schwartz PE, Morris JM. Serum lactic dehydrogenase: A tumor marker for dysgerminoma. Obstet Gynecol. 1988;72(3 Pt 2):511-515.
      17. Yoshimura T, Takemori K, Okazaki T, et al, Serum lactate dehydrogenase and its isoenzymes in patients with ovarian dysgerminoma . Int J Gynaecol Obstet. 1988, 27:459-465.
     18. Rotenberg Z, Weinberger I, Sagie A, et al, Total lactate dehydrogenase and its isoenzymes in serum of patients with non-small-cell lung cancer. Clin Chem. 1988,34:668-670.
     19. Manzo V, Sun T, and Lien YY. Misdiagnosis of acute myocardial infarction. Ann Clin Lab Sci. 1980,20(5):324-328.
     20. Galbraith LV, Leung FY, Jablonsky G, et al. Time-related changes in the diagnostic utility of total lactate dehydrogenase, lactate dehydrogenase isoenzyme-1, and two lactate dehydrogenase isoenzyme-1 ratios in serum after myocardial infarction. Clin Chem. 1990,36(7):1317-1322.
     21. Clark CP 3d, Foreman ML, Peters GN, et al. Efficacy of preoperative liver function tests and ultrasound in detecting hepatic metastasis in carcinoma of the breast. Surg Gynecol Obstet. 1988,167(6):510-514.
     22. Giannoulaki EE, Kalpaxis DL, Tentas C, et al. Lactate dehydrogenase isoenzyme pattern in sera of patients with malignant diseases. Clin Chem. 1989,35(3):396-399.

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