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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2593_Библиотеки_им_академика_М_И_Перельмана
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substrate per minute. The analogous expression in SI terms involves
the term katal (kat). One katal is the amount of enzyme to catalyze 1
mole of substrate per second, making 1.0 μkat the amount for 1.0
μmol/second. Based on this information, the conversion between
μkat and IU is 1 μkat—60 IU.
Creatine Kinase
Reference Range: Female, 20–170 IU/L or 0.33–2.83 μkat/L;
Male, 30–220 IU/L or 0.5–3.67 μkat/L
Creatine kinase (CK) catalyzes the transfer of high-energy
phosphate groups in tissues that consume large amounts of energy
(eg, skeletal muscle, myocardium, and brain). The serum
concentration of CK can be increased by strenuous exercise,
intramuscular injections of tissue-irritating drugs (eg, diazepam and
phenytoin), crush injuries, myocardial damage, rhabdomyolysis, or
high doses of certain HMG-CoA reductase inhibitors.
CK is composed of M and B subunits and is divided into three
isoenzymes: MM, BB, and MB. The CK-MM isoenzyme is found
predominantly in skeletal muscle, the CK-BB is predominantly in the
brain, and the CK-MB is predominantly in the myocardium.
Myocardial CK activity consists of 80% to 85% CK-MM and 15% to
20% CK-MB. Noncardiac tissues that contain large amounts of CK
have either CK-MM or CK-BB. The MB fraction is rare in tissues
other than in the myocardium, making it a more specific cardiac
marker.
CK-MB typically begins to increase 3 to 6 hours after an acute MI,
peaks at 12 to 24 hours, and accounts for about 5% or more of the
total CK.29 Myocardial damage appears to correlate with the amount
of CK-MB released into the serum (ie, the higher the amount of CKMB, the more extensive the myocardial injury). Although CK-MB
levels >25 IU/L are usually associated with an MI, the absolute
amount can vary, depending on the assay method.30 Generally, if the
amount of CK-MB exceeds 6% of the total CK, myocardial injury has
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presumably occurred. Analysis of CK-MB provides a rapid, sensitive,
specific, cost effective, and definitive means of detecting MI.
31
Troponin
Reference Range: Cardiac Troponin T (cTnT) 0–0.1 ng/mL or
μg/L; Cardiac Troponin I (cTnI) 0–0.3 ng/mL or μg/L; HighSensitivity Cardiac Troponin T (hs-cTnT) 0–14 ng/L; HighSensitivity Cardiac Troponin I (hs-cTnI) 0–6 ng/L
Troponins are proteins that regulate the calcium-mediated interaction
of actin and myosin within muscles. There are two cardiac-specific
troponins, cardiac troponin I (cTnI) and cardiac troponin T (cTnT).
cTnT is present in cardiac and skeletal muscle cells, whereas cTnI is
present only in cardiac muscle.
32,33
Although compared with the
detection of CK-MB, the presence of cTn is a more sensitive and
specific indicator of myocardial necrosis,34 it should be noted that
other conditions can cause an elevation in cTn (cardiac, renal,
pulmonary, etc). The concentration of cTn increases within 2 to 5
hours of an acute MI. On average, troponin remains elevated for
about 10 days compared with the 2- to 3-day elevation typically
observed with CK-MB. cTnI levels >0.3 ng/mL and cTnT levels >0.1
ng/mL are suggestive of acute myocardial tissue necrosis, but these
values may vary slightly by assay (because of lack of
standardization) and by institution. High-sensitivity cardiac troponin
(hs-cTn) can be employed for rapid MI rule-out or rule-in.35 Hs-cTn
can measure cTn at much lower concentrations than do older
conventional assays. There are several methods for MI rule-out
using these assays. One such method is the 0/2 method; an hs-cTn
should be drawn on arrival (0h) and again 2 hours later (2h).
35,36
These lab values are used in conjunction with all relevant clinical
data (eg, electrocardiogram [ECG], validated risk scores, and past
and current comorbid conditions) to help rule out MI. To be
considered a rule-out using the hs-cTnT, the levels at 0h and 2h
should be <14 ng/L and change from baseline at 2h should be <4
ng/L.
35,36
Using the hs-cTnI, the 0h and 2h levels should be <6 ng/L,
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and the change from baseline should be <2 ng/L.35 Patients who
present and do not completely fit the abovementioned criteria may
require a third hs-cTn lab test to confirm rule out. For rapid MI rulein, the patient would need to present with an hs-cTnT ≥53 ng/mL or
hs-cTnI ≥64 ng/L or have a change in hs-cTnT ≥10 ng/L or hs-cTnI
≥15 ng/L at 2h.35 Owing to differences in heart mass, estrogen
levels, and so on, females have lower baseline levels of circulating
hs-cTn. This has led to a proposal of using a lower cutoff for female
patients, but it remains controversial.
35–37
The reader is referred to
Chapter 13, Acute Coronary Syndrome, for a more detailed
discussion of the use of cardiac markers.
CASE 2-4
QUESTION 1: J.R., a 57-year-old male with a history of stable angina, presents
to a hospital emergency department. He has sudden-onset chest pressure and
tightness, diaphoresis, and nausea that has been waxing and waning for the
past few hours. J.R. describes his discomfort as severe at times and not
relieved by position change, antacids, or sublingual nitroglycerin. An ECG
reveals ST depressions consistent with myocardial ischemia. His cardiac
biomarkers reveal CK 220 IU/L, CK-MB 5%, hs-cTnT at 0h is 12 ng/L and at 2h
is 16 ng/L. Based on his presentation, ECG, and cardiac biomarkers, J.R. is
diagnosed with an MI (non–ST segment-elevation MI) and is admitted for a
cardiac catheterization.
Why are the total CK and CK-MB serum concentrations within the reference
range despite clear evidence, including elevated hs-cTnT, supporting an acute
MI?
Although CK and CK-MB are very helpful laboratory values for
identifying and assessing myocardial damage/necrosis, the utility of
these values alone can be quite limited. Troponin levels are very
sensitive and specific to myocardial cell death, can become positive
sooner than do CK and CK-MB, and will remain elevated for a much
longer period (up to 10 days). Even if the CK and CK-MB are not
elevated, the hs-cTnT can pick up even the smallest amount of
myocardial cell death. Based on the clinical picture and the elevated
troponin, the patient would be classified as having a non–ST
segment-elevation MI.
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Myoglobin
Reference Range: Female 12–76 μg/L; Male 19–92 μg/L
Myoglobin, a protein in heart and skeletal muscle cells, provides
oxygen to working muscles. Damaged muscle releases myoglobin
into the bloodstream. As a cardiac biomarker, myoglobin
concentrations in serum rise within 3 hours of insult to the
myocardial tissue, peak in about 8 to 12 hours, and return to normal
in about a day. Because myoglobin serum concentrations rise more
quickly than does CK-MB after myocardial injury, this parameter can
be of value in helping rule out MI in the emergency department.
Myoglobin serum concentrations, however, tend to be less specific
for myocardial tissue compared with CK-MB and troponin; trauma or
ischemic injury to noncardiac tissue can also increase serum
myoglobin.
Homocysteine
Reference Range: 4–12 μmol/L
Patients with deficiencies in folate, vitamin B6, or vitamin B12 tend to
have elevated serum levels of homocysteine. Homocysteine is
believed to have a destructive effect on vascular epithelium. With
time, patients with elevated homocysteine levels (>12 μmol/L) are
believed to be at increased risk for cardiac disease.38 Screening
individuals with a positive family history for elevated homocysteine or
those with premature atherosclerosis without typical risk factors has
been advocated. Understanding the association between increased
homocysteine levels and specific vitamin deficiencies,
supplementation of folate, vitamin B6, and vitamin B12 has been used
clinically. Although hyperhomocysteinemia may be an independent
risk factor for atherosclerosis, to date no studies have shown that
lowering homocysteine levels improves cardiovascular outcomes in
patients with preexisting atherosclerosis or cardiovascular disease
(CVD).
39
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Lactate Dehydrogenase
Reference Range: 100–250 IU/L (adult) or 1.67–4.17 μkat/L
The enzyme lactate dehydrogenase (LDH) is present in the heart,
kidney, liver, and skeletal muscle. It is also abundantly present in
erythrocytes and lung tissue. Because increased serum
concentrations of LDH can be associated with diseases in many
different organs and tissues, the diagnostic usefulness of an LDH
determination is somewhat limited. There are, however, five
isoenzymes of LDH. Although most tissues contain all five
isoenzymes, some tissues have a predominance of one of the
isoenzymes. LDH1 and, to a lesser extent, LDH2 predominate in the
heart. Skeletal muscle and the liver have a predominance of LDH5.
LDH3 and LDH4 are found in a variety of tissues, including the lungs,
RBCs, kidneys, brain, and pancreas. Consequently, identifying
specific isoenzymes can increase the diagnostic usefulness of serum
LDH determinations.
Brain Natriuretic Peptide
Reference Range: Brain Natriuretic Peptide (BNP) <100 pg/mL
or <100 ng/L: >500 pg/mL or >500 ng/L is considered elevated;
N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) <400
pg/mL or <400 ng/L: >2000 pg/mL or >2000 ng/L is considered
elevated.
BNP is released from the ventricles because of increased myocardial
demand. Elevations in BNP are indicative of patients with CHF and
volume overload. To reduce the workload on the heart, BNP
counteracts the renin–angiotensin–aldosterone system and causes
vasodilatory effects, along with natriuresis (increased excretion of
sodium), all geared at reducing blood volume. Patients with some
degree of CHF typically have BNP levels >100 ng/L. BNP levels
>500 ng/L represent definite CHF, but further evaluation is warranted
to more fully characterize the extent of impaired cardiac function.40 It
should be noted that BNP is a substrate of neprilysin and that use of
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an angiotensin receptor–neprilysin inhibitor (ARNI) can increase
BNP levels.41 This is not the case for NT-proBNP.42 NT-proBNP is a
by-product from the cleaving of pro-BNP to form BNP; it is also being
used in the clinical setting to assess HF. Similar to BNP, there are
three generally accepted ranges for NT-proBNP. Patients presenting
with an NT-proBNP level <400 ng/L are unlikely to have HF. A level
>2000 ng/L is indicative of an HF diagnosis, whereas values 400 to
2000 ng/L are considered uncertain. In both acute and ambulatory
HF, there is extensive evidence supporting the use of BNP and NTproBNP to aid in HF diagnosis; this is especially true in patients
presenting with shortness of breath of unknown etiology.
43–57
The
reader is referred to Chapter 14, Heart Failure, for a more detailed
discussion of the use of BNP and NT-proBNP.
C-Reactive Protein
Reference Range: 0–1.6 mg/dL or 0–16 mg/L
C-reactive protein (CRP) is a nonspecific, acute-phase reactant
helpful in the diagnosis and monitoring of inflammatory processes
(eg, rheumatoid arthritis and bacterial infections). CRP is produced
by the liver in response to inflammation. Although an elevation in
CRP indicates the presence of an acute inflammatory event, the
nonspecific nature of the test does little to identify the cause or
location of the inflammation. CRP is similar to an older test, the
erythrocyte sedimentation rate (ESR), but it tends to be more
sensitive than is ESR and is also associated with a more rapid and
greater response to acute inflammation. A potential use of CRP is as
a novel risk factor for CVD.58 CRP has also been used to assess
chronic inflammatory diseases such as rheumatoid arthritis and
Crohn disease. In addition, because viral infections do not typically
increase CRP serum concentrations, the use of CRP as a diagnostic
tool to differentiate viral from bacterial infections might be clinically
helpful. High-sensitivity CRP is a more sensitive test that has been
thought to be a better predictor of CVD risk and statin response, but
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its use remains controversial. Routine testing is not part of current
guidelines, and stratification and targets have not been validated.
59,60
LIVER FUNCTION TESTS
Aspartate Aminotransferase
Reference Range: 0–35 IU/L or 0–0.58 μkat/L
The AST enzyme is abundant in heart and liver tissue and
moderately present in skeletal muscle, kidney, and pancreas. In
cases of acute cellular injury to the heart or liver, the enzyme is
released into the blood from the damaged cells. In practice, AST
determinations have been used to evaluate myocardial injury and to
diagnose and assess the prognosis of liver disease resulting from
hepatocellular injury. The serum AST level is increased in >95% of
patients after an MI. However, the increase in AST does not occur
until 4 to 6 hours after the onset of myocardial injury. Peak AST
concentrations are seen in the serum after 24 to 36 hours, returning
to the normal range in about 4 to 5 days.
Serum AST values are elevated significantly in patients with acute
hepatic necrosis, whether caused by viral hepatitis or a hepatotoxin
(eg, carbon tetrachloride). In these situations, the serum
concentrations of both AST and alanine aminotransferase (ALT) will
be increased, even before the appearance of clinical symptoms (eg,
jaundice). The AST and ALT serum concentrations can be increased
by as much as 100 times the usual upper limits of normal in the
presence of parenchymal liver disease. Patients with intrahepatic
cholestasis, posthepatic jaundice, or cirrhosis usually experience
more moderate elevations of AST, depending on the extent of cell
necrosis. The AST serum concentration is usually higher than that of
ALT in patients with cirrhosis, and the AST increase is usually about
four to five times greater than is the upper limit of normal.
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Alanine Aminotransferase
Reference Range: 0–35 IU/L or 0–0.58 μkat/L
The ALT enzyme is found in essentially the same tissues that have
high concentrations of AST, but ALT is generally considered to be
more specific to the liver, because ALT concentrations in nonhepatic
tissues are low.61 Elevations in serum ALT are more specific for liverrelated injuries or diseases. Although ALT is relatively more
abundant in hepatic tissue versus cardiac tissue than is AST, the
liver still contains 3.5 times more AST than ALT. Serum
concentrations of both AST and ALT increase when disease
processes affect liver cell structure. Evaluating the ratio of ALT to
AST can be potentially useful, particularly in the diagnosis of viral
hepatitis. The ALT/AST ratio frequently exceeds 1.0 with alcoholic
cirrhosis, chronic liver disease, or hepatic cancer. However, ratios
<1.0 tend to be observed with viral hepatitis or acute hepatitis, which
can be useful when diagnosing liver disease.
62
Alkaline Phosphatase
Reference Range: 20–130 IU/L or 0.33–2.17 μkat/L
The alkaline phosphatases (ALPs) constitute a large group of
isoenzymes that play important roles in the transport of sugar and
phosphate. These isoenzymes of ALP have different physiochemical
properties and originate from different tissues (eg, liver, bone,
placenta, and intestine). In normal adults, ALP is derived primarily
from liver and bone and found in smaller quantities in the intestines,
kidneys, and white blood cells (WBCs).61 Although only small
amounts of ALP are present in the liver, this enzyme is secreted into
the bile, and substantially elevated ALP serum concentrations can
be seen with mild intrahepatic or extrahepatic biliary obstruction.
Thus, the presence of early bile duct abnormalities can result in
elevated ALP before increases in the serum bilirubin are observed.
Drug-induced cholestatic jaundice (eg, chlorpromazine or
sulfonamides) can increase serum ALP concentrations. In mild
cases of acute liver cell damage, ALP levels are seldom elevated.
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Even in cirrhosis, ALP concentrations are variable and depend on
the degree of hepatic decompensation and obstruction.
The osteoblasts in bone produce large amounts of ALP, and
marked serum elevations can be seen in Paget disease of the bone,
hyperparathyroidism, osteogenic sarcoma, osteoblastic cancer
metastatic to bone, and other conditions of pronounced osteoblastic
activity. The serum ALP is increased during periods of rapid bone
growth (eg, infancy, early childhood, and healing bone fractures) and
during pregnancy because of the contributions of the placenta and
fetal bones.
Gamma-Glutamyl Transferase
Reference Range: Male, 9–50 IU/L; Female, 8–40 IU/L
Although the enzyme γ-glutamyl transferase (GGT) is found in the
kidney, liver, intestine, prostate, and pancreas, its major clinical value
is in the evaluation of hepatobiliary disease. An increase in the
serum concentration of GGT parallels the increase of ALP in
obstructive jaundice and infiltrative disease of the liver. However,
increased ALP in the presence of a normal GGT is more suggestive
of muscular or bone-related issues, because GGT is not found in
bone. GGT is one of the more sensitive liver enzymes for identifying
biliary obstruction and cholecystitis. GGT can also be elevated in
patients with obesity.61 Because GGT is a hepatic microsomal
enzyme, tissue concentrations increase in response to microsomal
enzyme induction by alcohol and other drugs (eg, carbamazepine,
phenobarbital, and phenytoin). As a result, GGT is a sensitive
indicator of recent or chronic alcohol exposure.
Bilirubin
Total Bilirubin—Reference Range: 0.1–1.0 mg/dL or 2–18 μmol/L
Direct (Conjugated) Bilirubin—Reference Range: 0–0.2 mg/dL or
0–4 μmol/L
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Bilirubin is primarily a breakdown product of Hgb and is formed in the
reticuloendothelial system (Fig. 2-1, step 1). It is then transferred
into the blood (step 2), where it is almost completely bound to serum
albumin (step 3). When bilirubin arrives at the sinusoidal surface of
the liver cells, the free fraction is rapidly taken up into the cell (step
4) and converted primarily to bilirubin diglucuronide (step 5). A
monoglucuronide that is metabolized predominantly to the
diglucuronide is also formed. The conjugated bilirubin diglucuronide
is then excreted into the bile (step 6) and appears in the intestine,
where bacteria convert most of it to urobilinogen (step 7). The
majority of urobilinogen is destroyed or excreted in the feces (step
13), but a small portion is reabsorbed into the blood (step 8) and
either reabsorbed into the liver (step 9) and subsequently excreted
into the bile (step 12) or excreted into the urine (step 10).
Urobilinogen is responsible for the straw color of the urine and the
yellowish-brown color of the feces. The mechanism by which
conjugated bilirubin in the liver cell is transferred to the blood (step
14) is not well understood. However, in many types of liver disease,
conjugated (direct) bilirubin is present in increased concentrations in
the blood. When this concentration exceeds 0.2 to 0.4 mg/dL,
bilirubin will begin to appear in the urine (step 11). Unconjugated
(indirect) bilirubin is water insoluble and is highly bound to serum
albumin; both factors account for its lack of excretion in the urine.
63
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