Lactic dehydrogenase (LDH) values refer to total serum LDH. Total LDH levels are elevated at some time in 92%-95% (literature range, 82%-100%) of patients with acute MI. Statistics for sensitivity in acute MI refer to multiple sequential LDH specimens and are therefore not valid for any single determination. In acute MI, LDH becomes elevated 24-48 hours after MI, reaches a peak 48-72 hours after MI, and slowly falls to normal in 5-10 days. Thus, LDH values tend to parallel AST values at about double the time interval. Total LDH is slightly more sensitive than AST in acute MI and is reported to be elevated even in small infarcts that show no AST abnormality.

LDH is found in many organs and tissues. In acute liver cell damage, the total LDH value is not as sensitive as the AST value. In mild acute or chronic passive congestion of the liver, the LDH level is frequently normal or only minimally increased. In moderate or severe congestion, LDH values range from mild to substantial degrees of elevation.

Since LDH fraction 1 is contained in red blood cells (RBCs) as well as cardiac muscle, LDH is greatly influenced by accidental hemolysis in serum and thus must be collected and transported with care. Heart valve prostheses may produce enough low-grade hemolysis to affect LDH, and LDH levels are also abnormal in many patients with megaloblastic and moderate or severe hemolytic anemias. Skeletal muscle contains LDH, so total LDH (or even hydroxybutyric acid dehydrogenase [HBD]) values are not reliable in the first week after extensive surgery. LDH levels may be elevated in 60%-80% of patients with pulmonary embolism (reports vary from 30%-100%), possibly due to pulmonary tissue damage or to hemorrhage.

Finally, LDH becomes elevated in some patients with malignant neoplasms and leukemia, and in some patients with uremia.

The major drawback of total LDH, similar to AST, is the many conditions that can elevate LDH values.

LDH sites of origin
Skeletal muscle

Lactic dehydrogenase isoenzymes. Total LDH is actually a group of enzymes. The individual enzymes (isoenzymes) that make up total LDH have different concentrations in different tissues. Therefore, the tissue responsible for an elevated total LDH value may often be identified by fractionation (separation) and measurement of individual isoenzymes. In addition, since the population normal range for total LDH is rather wide, abnormal elevation of one isoenzyme may occur without lifting total LDH out of the total LDH normal range.

Five main fractions (isoenzymes) of LDH are measured. With use of the standard international nomenclature (early U.S. investigators used opposite terminology), fraction 1 is found mainly in RBCs and in heart and kidney, fraction 3 comes from lung, and fraction 5 is located predominantly in liver and to a lesser extent in skeletal muscle. Skeletal muscle contains some percentage of all the fractions, although fraction 5 predominates. Various methods of isoenzyme separation are available. The two most commonly used are heat and electrophoresis. Heating to 60°C for 30 minutes destroys most activity except that of fractions 1 and 2, the heat-stable fractions. With electrophoresis, the fast-moving fractions are 1 and 2 (heart), whereas the slowest-migrating fraction is 5 (liver). Electrophoresis has the advantage that one can see the relative contribution of all five fractions. Immunologic methods to detect LDH-1 are also available.

The relative specificity of LDH isoenzymes is very useful because of the large number of diseases that affect standard heart enzyme tests. For example, one study of patients in hemorrhagic shock with no evidence of heart disease found an elevated AST level in 70%, an elevated total LDH level in 52%, and an elevated alanine aminotransferase (ALT); (formerly serum glutamate pyruvate transaminase) level in 37%. LDH enzyme fractionation offers a way to diagnose MI when liver damage is suspected of contributing to total LDH increase. In liver damage without MI, fraction 1 is usually normal, and most of the increase is due to fraction 5.

Several characteristic LDH isoenzyme patterns are illustrated in Fig. 21-1. However, not all patients with the diseases listed necessarily have the “appropriate” isoenzyme configuration; the frequency with which the pattern occurs depends on the particular disease and the circumstances. Multiorgan disease can be a problem since it may produce combinations of the various patterns. For example, in acute MI the typical pattern is elevation of LDH-1 values with LDH-1 values greater than LDH-2. However, acute MI can lead to pulmonary congestion or hypoxia, with elevation of LDH-2 and LDH-3 values, and may also produce liver congestion or hypoxia, with elevation of LDH-4 and LDH-5 values. Acute MI can also produce multiorgan hypoxia or shock. In shock all LDH fractions tend to be elevated, and in severe cases the various fractions tend to move toward equal height. In malignancy, there may be midzone elevation only, elevation of only fraction 4 and 5, or elevation of all fractions. In my experience, the most common pattern in malignancy is elevation of all fractions with normal relationships preserved between the fractions.

Fig. 21-1 Representative LDH isoenzyme patterns with most frequent etiologies. A, normal. B, Fraction 1 increased with fraction 1 greater than fraction 2: acute MI; artifactual hemolysis; hemolytic or megaloblastic anemia (cellulose acetate method, not agarose gel); renal cortex infarct; germ cell tumors. C, Fraction 5 increased: acute hepatocellular injury (hepatitis, passive congestion, active cirrhosis, etc); acute skeletal muscle injury. D, Fractions 2 and 3 elevated: pulmonary hypoxia (pulmonary embolization, cardiac failure, extensive pneumonia, etc); pulmonary congestion, lymphoproliferative disorders, myeloma, viral pulmonary infection. E, Fractions 2 through 5 elevated: lung plus liver abnormality (pulmonary hypoxia and/or congestion plus liver congestion, infectious mononucleosis or cytomegalovirus infection, lymphoproliferative disorders). F, All fractions elevated, relatively normal relationships preserved between the fractions (fraction 5 sometimes elevated disproportionately): multiorgan hypoxia and/or congestion (with or without acute MI); malignancy; occasionally in other disorders (trauma, infection/inflammation, active cirrhosis, chronic obstructive pulmonary disease, uremia, etc.)

The LDH isoenzymes may be of help in evaluating postsurgical chest pain. Skeletal muscle mostly contains fraction 5 but also some fraction 1, so total LDH, HBD, or fraction 1 elevations are not reliable during the first week after extensive surgery. However, a normal LDH-1 value in samples obtained both at 24 and 48 hours after onset of symptoms is considerable evidence against acute MI, and an elevation of the LDH-1 value with the LDH-1 value greater than LDH-2 is evidence for acute MI. However, there have been reports that some athletes engaged in unusually strenuous (e.g., distance running) activity had reversal of the LDH-1/LDH-2 ratio after completing a race, and one report found that almost half of a group of highly trained star college basketball players had reversed LDH-1/LDH-2 ratios at the beginning of team practice for the basketball season. CK isoenzyme levels, if available, are of greater assistance than LDH isoenzyme levels in the first 24 hours.

Immunoassay methods are now available for measurement of LDH-1 alone. Measurement of LDH-1 has been claimed to be superior to the LDH-1/LDH-2 ratio in diagnosis of acute MI. The typical reversal of the LDH-1/LDH-2 ratio is found in only 80%-85% of patients (literature range, 61%-95%) with acute MI. In some cases, reversal of the ratio is prevented (masked) by an increase of LDH-2 values due to pulmonary hypoxia occurring concurrently with the increase of LDH-1 values due to MI. An elevated LDH-1 fraction as demonstrated on immunoassay is more sensitive (detection rate about 95%; literature range, 86%-100%) than reversal of the LDH-1/LDH-2 ratio in acute MI. However, in my experience and that of others, LDH-1 values can be increased in myocardial hypoxia without any definite evidence of acute MI (e.g., in hypovolemic shock). In addition, the LDH-1 value by immunoassay is increased by all the noncardiac conditions that reverse the LDH-1/LDH-2 ratio (hemolytic or megaloblastic anemia, renal cortex infarct). Thus, the increase in sensitivity gained by LDH-1 immunoassay in acute MI must be weighed against the possible loss of specificity(increase in LDH-1 values not due to acute MI, see the box on this page). LDH isoenzyme fractionation by electrophoresis also demonstrates increased LDH-1 values even when the LDH-1/LDH-2 ratio is not reversed.

Most LDH fractions are stable for several days at refrigerator temperature. If the specimen is frozen, LDH-5 rapidly decreases.