Lactate Dehydrogenase (LD) Isoenzymes

Serum

2 mL

1 mL (Note: This volume does not allow for repeat testing.)

Red-top tube or gel-barrier tube

Cardiac enzymes and isoenzymes are best interpreted as a sequential series. Typically, a series of three: one at admission (or initial event) and two more at six- to eight-hour intervals.

Lactate dehydrogenase (LD) is an enzyme that is found in almost all of the body's cells, but only a small amount of it is usually detectable in the blood. LD is released from the cells into the bloodstream when cells are damaged or destroyed. Because of this, the LD test can be used as a general marker of injury to cells.

Although there is some overlap, each of the five LD isoenzymes tends to be concentrated in specific body tissues. In general, the isoenzyme locations are as follows:

• LD₁: Heart, red blood cells, kidney

• LD₂: Heart, red blood cells, kidney (lesser amounts than LD₁)

• LD₃: Lungs and other tissues

• LD₄: White blood cells, lymph nodes, muscle, liver (lesser amounts than LD₅)

• LD₅: Liver, skeletal muscle

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 the 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 an 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 to 24 hours after onset of infarction, LD isoenzymes usually become diagnostic at about 36 to 55 hours after onset and return to normal between 3 and 14 days after onset.

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.

Electrophoresis

• Total: See table.

• LD₁: 17% to 32%

• LD₂: 25% to 40%

• LD₃: 17% to 27%

• LD₄: 5% to 13%

• LD₅: 4% to 20%

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 LD₁ and 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 to 12 hours prior to venipuncture.

• Case 4: The LD isoenzyme pattern demonstrates LD₁ greater 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 LD₂ and 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 LD₄ and 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 isoenzymes 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. The LD total is significantly elevated, and there is no increase in the relative percentage of any fraction. The LD isoenzyme pattern is an "isomorphic pattern." This pattern may be seen with neoplasia, cardiorespiratory diseases, hypothyroidism, infectious mononucleosis, and other inflammatory states, uremia, and necrosis.

• 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.

Patterns of LD isoenzymes in acute pulmonary edema include the isomorphic pattern and LD₅ increases.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 is 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 Increased 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.