injury is whether release of the substances can occur
when the damage to the cells is reversible or if
marker release signifies cell death. In the case of
hepatocytes, marker release clearly can occur while
cell injury is still reversible (Schmidt and Schmidt
1987). Mild injury causes some release of cyto-
plasmic substances. The more severe the injury, the
greater the amount of cytoplasmic material, includ-
ing cytoplasmic injury markers, released. With very
severe injury, cell death is frequent leading to the
release of intracellular substances contained within
membrane-bound organelles such as the mitochon-
dria and lysosomes (Karmiike
et al.
1989). For
example, only small amounts of the intramitochon-
drial enzyme glutamate dehydrogenase are released
in the course of typical acute viral hepatitis whereas
abundant amounts are liberated in cases of fulminant
hepatic necrosis.
Even though various cell and tissue culture
studies have shown that cytoplasmic substances can
be lost following reversible cellular injury (Schmidt
and Schmidt 1987), clinical findings suggest that
marker release is highly specific for cell death in
some settings. The acute cardiac myocyte response
to ischemia is the most important example: eleva-
tions in the tissue-specific cardiac injury markers
appear to occur only when there is some degree of
myocardial necrosis.
Tissue specificity
For a substance to serve as a specific plasma
marker of tissue injury, it is necessary that the
substance arise predominantly from the cells of the
organ or tissue of interest. Otherwise, injury to
other tissues containing the substance will cause its
release into the circulation. This release will either
be misinterpreted as resulting from injury to the
tissue of interest when there is none or will interfere
with the interpretation of plasma levels of the
substance when there is concurrent injury.
Highly specific markers have been identified for
a number of tissues. A few are unique cell products,
e.g., hemoglobin which is found only in red cells
and red cell precursors; some are enzymes found
predominantly in the specialized tissue, e.g., lipase
most of which arises from the pancreas; and some
are tissue-specific isoenzymes of widely distributed
enzymes, e.g., the pancreatic isoenzymes of
α
-amylase. Isoenzymes are proteins that catalyze
the same reaction but differ from one another in
their structure. In the case of
α
-amylase, the
isoenzymes arise from differences in posttrans-
lational carbohydrate modifications of the enzyme.
Even if there is not a high degree of tissue specific-
ity for the isoenzymes of a given enzyme, mathe-
matical techniques of data analysis may be able to
quantify the contribution made by a specific tissue to
the total plasma pool of the enzyme (Politser
et al.
1986).
The total concentration of an enzyme can usually
be assayed much more quickly and easily than can
the concentration of the corresponding tissue-specific
isoenzyme. This makes the measurement of total
enzyme concentration useful in emergent clinical
situations where speed in obtaining a usable result is
more important than obtaining a highly specific
result. Because total enzyme concentrations are
usually sensitive markers of tissue injury, they can
also be used to identify those specimens that merit
the performance of an expensive and difficult isoen-
zyme determination. Furthermore, in uncomplicated
clinical situations, total enzyme concentrations enjoy
quite acceptable diagnostic specificity despite their
inferior tissue specificity.
Table 9.1 lists plasma markers of myocardial
injury and categorizes the degree of tissue specificity
of each (Keffer 1996 and 1997, Bhayana and
Henderson 1995). Aspartate aminotransferase was
once the standard marker in the diagnosis of acute
myocardial infarct but it is widely distributed in
body tissues and consequently has low cardiac speci-
ficity. It has been supplanted by creatine kinase.
Creatine kinase is a two subunit enzyme, the isoen-
zymes of which are made up of homo- or hetero-
dimers of M and B protein subunits. Cardiac muscle
expresses both the M subunit and the B subunit; the
M subunit is expressed at a higher level than the B
subunit so creatine kinase-MM is the majority intra-
cellular isoenzyme; the ratio of creatine kinase-MM
to creatine kinase-MB is approximately 5 to 1.
Skeletal muscle expresses the M subunit and the B
subunit but the B subunit is expressed at very low
levels so that skeletal muscle creatine kinase consists
overwhelmingly of creatine kinase-MM. Following
muscle injury, the plasma concentration of total
creatine kinase increases as a result of the release of
creatine kinase-MM; the plasma concentration of
creatine kinase-MB increases relatively little except
when the muscle injury is massive. Following
cardiac injury, the release of creatine kinase-MM
and creatine kinase-MB cause the plasma concentra-
tions of both to increase. In the absence of skeletal
Tissue Injury
9-2
