Articles on Medical Diseases and Conditions

Tag: Lactic dehydrogenase

  • Lactic Dehydrogenase

    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
    Heart
    Liver
    Skeletal muscle
    RBCs
    Kidney
    Neoplasia
    Lung
    Lymphocytes

    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.

  • Lactic Dehydrogenase (LDH)

    Lactic dehydrogenase (LDH) is found in heart, skeletal muscle, and RBCs, with lesser quantities in lung, lymphoid tissue, liver, and kidney. A considerable number of conditions can elevate total LDH levels. For that reason, serum total LDH has not been very helpful as a liver function test. However, in some cases isoenzyme fractionation by electrophoresis of elevated total LDH can help indicate the origin of the elevation and therefore help interpret the total liver function test pattern. For unknown reasons, LDH is a relatively insensitive marker of hepatic cell injury, with values usually remaining less than 3 times the upper reference limit even in acute hepatitis virus hepatitis. However, occasional patients with hepatitis virus hepatitis, infectious mononucleosis, and severe liver damage from other causes may have values greater than 3 times the upper limits. Metastatic liver tumor sometimes is associated with very high LDH values, presumable due to the widespread tumor.

    LDH can be fractionated into five isoenzymes using various methods. The electrophoretically slowest moving fraction (fraction 5) is found predominantly in liver and skeletal muscle. Compared to total LDH, the LDH-5 fraction is considerably more sensitive to acute hepatocellular damage, roughly as sensitive as the AST level, and is more specific. Degree of elevation is generally less than that of AST.

  • Laboratory Tests in Hemolytic Anemias

    Certain laboratory tests are extremely helpful in suggesting or demonstrating the presence of hemolytic anemia. Which tests give abnormal results, and to what degree, depends on the severity of the hemolytic process and possibly on its duration.

    Reticulocyte count. Reticulocyte counts are nearly always elevated in moderate or severe active hemolytic anemia, with the degree of reticulocytosis having some correlation with the degree of anemia. The highest counts appear after acute hemolytic episodes. Hemolytic anemia may be subclinical, detected only by RBC survival studies, or more overt but of minimal or mild intensity. In overt hemolytic anemia of mild intensity the reticulocyte count may or may not be elevated. Studies have found reticulocyte counts within reference range in 20%-25% of patients with hemolytic anemia, most often of the idiopathic autoimmune type. In one study of 35 patients with congenital spherocytosis, reticulocyte counts were normal in 8.5% of patients; and in one study of patients with thalassemia minor, reticulocyte counts were less than 3% in one half of the patients. Nevertheless, the reticulocyte count is a valuable screening test for active hemolytic anemia, and reticulocyte counts of more than 5% should suggest this diagnosis. Other conditions that give similar reticulocyte response are acute bleeding and deficiency anemias after initial treatment (sometimes the treatment may be dietary only). It usually takes 2 to 3 days after acute hemolysis or bleeding for the characteristic reticulocyte response to appear, and occasionally 4 or 5 days if the episode is relatively mild.

    Lactic dehydrogenase. Total serum lactic dehydrogenase (LDH) consists of a group of enzymes (isoenzymes) that appear in varying amounts in different tissues. The electrophoretically fast-migrating fraction LDH-1 is found in RBCs, myocardial muscle fibers, and renal cortex cells. RBC hemolysis releases LDH-1, which elevates LDH-1 values and usually increases total LDH values. The LDH measurement is a fairly sensitive screening test in hemolytic disease, probably as sensitive as the reticulocyte count, although some investigators believe that LDH results are too inconsistent and unreliable in mild disease. Other conditions that increase LDH-1 levels include artifactual hemolysis from improper venipuncture technique or specimen handling, megaloblastic anemia, and acute myocardial infarction. In addition, the total LDH value may be elevated due to an increase in one of the other LDH isoenzymes, especially the liver fraction. Therefore, nonspecificity has limited the usefulness of total LDH values in the diagnosis of hemolytic anemia. The LDH-1 assay is more helpful. A normal total LDH value, however, would assist in ruling out hemolytic anemia if the degree of anemia were substantial. The LDH-1/LDH-2 ratio is reported to be reversed in about 60% of patients with hemolytic anemia when the lab uses electrophoresis on cellulose acetate and may or may not occur using agarose gel, depending on the method. According to one study, reversed LDH-1/LDH-2 ratio is more likely to occur in hemolytic episodes if there is a substantial degree of reticulocytosis.

    Serum haptoglobin. Haptoglobin is an alpha-2 globulin produced by the liver that binds any free hemoglobin released into the blood from intravascular or extravascular RBC destruction. Haptoglobin can be estimated in terms of haptoglobin-binding capacity or measured by using antihaptoglobin antibody techniques (Chapter 11). Under ordinary conditions a decreased serum haptoglobin level suggests that hemolysis has lowered available haptoglobin through binding of free hemoglobin. Total haptoglobin levels decrease within 8 hours after onset of hemolysis.

    The usefulness of serum haptoglobin levels in the diagnosis of hemolytic conditions is somewhat controversial, although the haptoglobin level is generally considered to have a sensitivity equal to or better than that of the reticulocyte count. The actual sensitivity for minimal or mild hemolytic disease is not well established. There are reports that haptoglobin values may be normal in 10%-20% of cases. Serum haptoglobin levels have been used to differentiate reticulocytosis due to hemolytic anemia from reticulocytosis due to acute bleeding or iron deficiency anemia under therapy. However, some reports indicate that occasionally haptoglobin levels may be mildly decreased in patients with iron deficiency anemia not known to have hemolytic anemia. Most patients with megaloblastic anemia have decreased haptoglobin levels. Haptoglobin levels also may be decreased in severe liver disease, from extravascular hematomas (due to absorption of hemoglobin into the vascular system), and with estrogen therapy or pregnancy. Congenital absence of haptoglobin occurs in approximately 3% of African Americans and about 1% (range, less than 1%-2%) of Europeans. About 80%-90% of newborns lack haptoglobin after the first day of life until 1-6 months of age. Haptoglobin is one of the “acute-phase reaction” serum proteins that are increased in conditions such as severe infection, tissue destruction, acute myocardial infarction, and burns, and in some patients with cancer; these conditions may increase the haptoglobin level sufficiently to mask the effect of hemolytic anemia or a hemolytic episode.

    Plasma methemalbumin. After the binding capacity of haptoglobin is exhausted, free hemoglobin combines with albumin to form a compound known as methemalbumin. This can be demonstrated with a spectroscope. The presence of methemalbumin means that intravascular hemolysis has occurred to a considerable extent. It also suggests that the episode was either continuing or relatively recent, because otherwise the haptoglobins would be replenished and would once again take over the hemoglobin removal duty from albumin.

    Free hemoglobin in plasma or urine. Circulating free hemoglobin occurs when all of the plasma protein-binding capacity for free hemoglobin is exhausted, including albumin. Normally there is a small amount of free hemoglobin in the plasma, probably because some artifactual hemolysis is unavoidable in drawing blood and processing the specimen. This is less when plasma is used instead of serum. If increased amounts of free hemoglobin are found in plasma, and if artifactual hemolysis due to poor blood-drawing technique (very frequent, unfortunately) can be ruled out, a relatively severe degree of intravascular hemolysis is probable. Marked hemolysis is often accompanied by free hemoglobin in the urine (hemoglobinuria). In chronic hemolysis, the urine may contain hemosiderin, located in urothelial cells or casts.

    Direct Coombs’ test. This test is helpful when a hemolytic process is suspected or demonstrated. It detects a wide variety of both isoantibodies and autoantibodies that have attached to the patient’s RBCs (see Chapter 9). The indirect Coombs’ test is often wrongly ordered in such situations. The indirect Coombs’ test belongs to a set of special techniques for antibody identification and by itself is usually not helpful in most clinical situations. If antibody is demonstrated by the direct Coombs’ test, an antibody identification test should be requested. The laboratory will decide what techniques to use, depending on the situation.

    Serum unconjugated (indirect-acting) bilirubin. The serum unconjugated bilirubin level is often elevated in hemolysis of at least moderate degree. Slight or mild degrees of hemolysis often show no elevation. The direct-acting (conjugated) fraction is usually elevated to less than 1.2 mg/100 ml (2.05 µmol/L) and less than 30% of total bilirubin unless the patient has coexisting liver disease. Except in blood bank problems, serum bilirubin is not as helpful in diagnosis of hemolytic anemias as most of the other tests and often shows equivocal results.

    Red blood cell survival studies. RBC survival can be estimated in vivo by tagging some of the patient’s RBCs with a radioactive isotope, such as chromium 51, drawing blood samples daily for isotope counting, and determining how long it takes for the tagged cells to disappear from the circulation. Survival studies are most useful to demonstrate low-grade hemolytic anemias, situations in which bone marrow production is able to keep pace with RBC destruction but is not able to keep the RBC count at normal levels. Low-grade hemolysis often presents as anemia whose etiology cannot be demonstrated by the usual methods. There are, however, certain drawbacks to this procedure. If anemia is actually due to chronic occult extravascular blood loss, radioisotope-labeled RBCs will disappear from the circulation by this route and simulate decreased intravascular survival. A minor difficulty is the fact that survival data are only approximate, because certain technical aspects of isotope RBC tagging limit the accuracy of measurement.