CLINICAL PATHOLOGY 0749-0739/95 $0.00 + .

20

INTERPRETATION OF
EQUINE SERUM BIOCHEMICAL
PROFILE RESULTS
Steven L. Stockham, DVM, MS

A serum biochemical profile (or panel) is a group of chemical assays

that are used to analyze biochemical constituents of serum. Assays
included in a biochemical profile will vary with the purpose of the
diagnostic procedure and between laboratories. For example, a liver
biochemical profile might include hepatic enzyme, protein, and total
bilirubin assays; however, a complete equine profile might include all
assays completed on a laboratory's automated instrument that are of
any potential value in horses. Manual assays or bench top assays usually
are not part of profiles of reference laboratories and thus are not dis­
cussed in this article.
Submission of serum for a biochemical profile is a routine part of
the diagnostic evaluation of many equine cases. As with most diagnostic
procedures, pertinent patient history information and physical examina­
tion results are needed to optimize the value of laboratory test results.
Results from a profile can be used to scan many body systems for
presence of a pathologic state or can be used to pursue or confirm
specific diagnoses. Because of savings associated with batch or profile
analysis, it may be more economical to request a serum biochemical
profile than to request a few specific chemistry tests.
This article contains introductory concepts and basic interpretative
information for serum analytes that are measured by major veterinary
reference laboratories. The results that are calculated from measured
values also are discussed.

From the Department of Veterinary Pathobiology, College of Veterinary Medicine, Univer­

sity of Missouri-Columbia, Columbia, Missouri

VETERINARY CLINICS OF NORTH AMERICA: EQUINE PRACTICE

VOLUME 11 • NUMBER 3 • DECEMBER 1995 391

392 STOCKHAM

SAMPLE QUALITY
Results of a serum biochemical assays are only as good as the
sample. Venous blood samples should be collected into clean glass tubes
and kept at room temperature to allow time for clot formation and
retraction (usually 30 to 60 minutes). After centrifugation of clotted
blood, serum is transferred to a clean sample submission container
labeled with animal identification information. The sample should be
kept cool (in refrigerator or shipped with freezer packs) and submitted
to a laboratory within 24 hours. For longer sample submission periods,
serum may be frozen without damaging analytes that are common in
profiles. Repeated thawing and freezing is discouraged because it may
damage proteins.
Poor sample collection and handling techniques can cause erroneous
assay results. Equine serum should be clear with a slight yellow tint. If
a sample is hemolyzed (pink to red), lipemic (hazy to creamy white
because of lipids), or icteric (dark yellow to orange), the sample may
not be adequate for certain biochemical assays (especially spectrophoto­
metric procedures). Degree of interference caused by hemoglobin, lipids,
or bilirubin, however, will vary among assay systems. Veterinarians
should establish a strong professional relationship with a reference labo­
ratory so that they can ask laboratory personnel if hemolysis, lipemia,
or icterus interferes with certain assays when the need occurs.

REFERENCE INTERVALS
Reference intervals for serum biochemical assays include the range
of results that are expected in healthy animals. Even though commonly
stated, the terms normal value or normal range should be discouraged
because a healthy horse's value may be outside of a reference interval.
A reference interval for a given analyte may vary among laboratories
because of different analytical methods, horses (age, breed, gender)
included in the reference population, or methods used to select the
central 95% of all measured reference values. Also, not all laboratories
use the same units of measure for reporting results. For example, one
laboratory might use conventional units for most analytes (i.e., mg/dL,
mEq/L), whereas another may use Systeme International (SI) units (i.e.,
mmol/L, µ,mol/).
To interpret your patient's profile results, you should know if the
reference interval provided by a laboratory is appropriate for compari­
son. Usually, reported reference intervals are for healthy adult animals.
Foal values are expected to be higher than adult values for some analytes
(alkaline phosphatase, aspartate transaminase, bilirubin, cholesterol, -y-glu­
tamyltransferase, glucose, phosphorus, potassium, triglyceride), but lower
values are expected for other analytes (albumin, chloride, creatinine, globu­
lins, glucose, total protein, urea). 9• 10• 36 When in doubt, veterinarians should
call the laboratory that analyzed a patient's sample to determine if the
provided reference intervals are appropriate for comparison.
As well-defined reference intervals represent the central 95% of all
 INTERPRETATION OF EQUINE SERUM BIOCHEMICAL PROFILE RESULTS 393

measured values found in healthy animals, 1 of 20 results from a healthy

animal should be outside the reference interval. Typically, this abnormal
result from a normal animal will be only mildly increased or decreased;
therefore, veterinarians should be careful not to over interpret slightly
"abnormal" test results. On the other hand, slightly "abnormal" test
results might be the only biochemical evidence of a pathologic state in
a patient.

GENERAL SERUM ANALYTES

Urea and Creatinine

Urea concentration is commonly reported as blood urea nitrogen

(BUN) or occasionally as serum urea nitrogen (SUN), or urea nitrogen
(UN) concentration.* Two major processes alter serum urea concentra­
tions; these are the rate of urea synthesis by hepatocytes and the rate of
urea clearance by kidneys. Rate of urea synthesis primarily depends on
hepatic function and is influenced by alterations in protein diet or
catabolism. Rate of urea renal clearance depends on glomerular filtration
rate (GFR) and rate of urea resorption by renal tubules.
Creatinine is another nonprotein nitrogen compound that com­
monly is measured in serum. Creatinine is formed from the degradation
of creatine in muscle. Like urea, serum creatinine concentrations depend
on the rate of synthesis and rate of excretion. Rate of synthesis, however,
is relatively constant except when rhabdomyolysis or marked muscular
exertion is present. Renal excretion of creatinine is highly dependent on
the GFR; unlike urea, creatinine is not resorbed by renal tubules.44
Serum urea and creatinine concentrations are measured routinely
to detect disorders that cause azotemia (increased concentrations of
nonprotein nitrogen compounds). Azotemia usually is caused by a
pathologic state that produces a decreased GFR. Decreased GFR can be
the result of prerenal, renal, or postrenal mechanisms that lead to the
classification of prerenal, renal, or postrenal azotemias. There must be a
marked reduction in GFR before urea or creatinine accumulate in blood.
There are probably at least two reasons for this: (1) kidneys have a
marked functional reserve and (2) urea and creatinine also are excreted
via the intestinal tract. The intestinal degradation of urea and the absorp­
tion of ammonium may result in a futile excretory process.42
Low serum urea concentrations can be found after prolonged diure­
sis, marked hepatic dysfunction, and also have been reported a few
days after prolonged halothane anesthesia.119 There is no diagnostic
significance to decreased serum creatinine concentrations.

*A urea concentration of 60 mg/dL equals a UN concentration of 28 mg/dL because

a mole of urea weighs 60 g and contains 28 g of nitrogen. As urea concentrations
within and outside of blood cells are the same, BUN concentrations will equal SUN
concentrations.
394 STOCKHAM

Prerenal Azotemia
Prerenal azotemia usually is caused by a disorder that causes de­
creased renal blood flow such as dehydration, hypovolemia, or de­
creased cardiac output. Also, azotemia created by endotoxic shock is at
least partially the result of poor renal perfusionY 8 As a result of dehy­
dration or hypovolemia, stimulation of hypothalamic-pituitary system
or renin-angiotensin system can cause release of antidiuretic hormone
(ADH) and/or aldosterone, respectively. Aldosterone will stimulate the
retention of sodium that in turn leads to a higher plasma osmolality and
thus more ADH release. In presence of a tubular/medullary osmotic
gradient, ADH will promote resorption of water in the distal nephron
(distal convoluted tubules and collecting ducts). Enhanced water resorp­
tion will cause formation of urine with higher urine specific gravity
(USG) values (expect USG > 1.020). Also, ADH promotes enhanced
tubular resorption of urea in intermedullary collecting ducts and thus
will augment the degree of azotemia caused by decreased GFR.82
Other findings that support a conclusion of prerenal azotemia
would be historic or physical evidence of dehydration, hypovolemia, or
decreased cardiac output. Other abnormalities that reflect hemoconcen­
tration and can be detected by laboratory assays include erythrocytosis
(increased packed cell volume, increased hemoglobin concentration, or
increased red blood cell count) and hyperproteinemia (with or without
concurrent hyperalbuminemia or hyperglobulinemia). Electrolyte abnor­
malities (hyponatremia, hyperkalemia, hypochloremia, hyperphospha­
temia) have been reported in cases for which the azotemia was consid­
ered to be of prerenal origin.19 Not all reported abnormalities, however,
could be easily attributed to prerenal mechanisms.
In theory, prerenal azotemia also can be caused by increased urea
or creatinine synthesis. Increased urea synthesis may occur whenever
there is increased protein catabolism or increased dietary protein or
ammonium. There is usually sufficient excretory reserve capacity in
animals, however, so that increased urea synthesis by itself will not
cause azotemia. Urea concentration can be slightly higher due to higher
protein intake,31• 79• 91• 96 and diets with high urea content can cause a mild
azotemia.95

Renal Azotemia
Renal azotemia is caused by either an acute or chronic renal disease
that damages functional nephrons and thus decreases GFR. There must
be marked reduction in renal functional tissue (estimated 60%-75%
loss) before azotemia occurs. Accordingly, serum urea and creatinine
concentrations have poor diagnostic sensitivity for renal disease, but
they are the major indicators for renal dysfunction.
If renal disease is the result of a chronic process (e.g., chronic
glomerulonephritis or pyelonephritis,2• 121 amyloidosis, polycystic kidney
disease,16• 110 renal hypoplasia,4• 140 or nephrolithiasis59 ), azotemia is ac-
 INTERPRETATION OF EQUINE SERUM BIOCHEMICAL PROFILE RESULTS 395

companied by a decreased renal concentrating ability and (depending

on the degree of dysfunction) either polyuria, oliguria, or anuria. A
horse's USG will be lower than expected and may be in the isosthenuric
range. Isothenuria is a state in which the urine and plasma osmolalities
are nearly equal. When isosthenuria is present, a horse's USG frequently
will be between 1.008 to 1.012. A USG above or below that range does
not exclude the possibility that isosthenuria is present.
If renal disease is the result of an acute process (e.g., vitamin K3
toxicosis, red maple leaf toxicosis, myogloblin nephrosis, phenylbuta­
zone toxicosis,71 or gentamicin toxicosis99 ), a horse's USG will vary
depending on the degree of renal damage and stage of the nephrosis.
Typically, urine volume will be decreased in early stages. Urine sedi­
ment examination may detect cylindruria.
Other laboratory evidence of acute or chronic renal disease may
include hypercalcemia, hypophosphatemia, hyponatremia, hypochlore­
mia, hyperkalemia, increased fractional excretion of sodium or phospho­
rus, and increased urinary excretion of gamma glutamyltransferase
(GGT).12

Postrenal Azotemia
Postrenal azotemia is due to a pathologic state that causes impaired
excretion of urine, e.g., urinary system blockage or leakage of urine into
abdominal cavity.13· 89• 126 In urinary obstructions, increased intracapsular
hydrostatic pressure within glomeruli and constriction of afferent glo­
merular arterioles cause decreased GFR and thus azotemia. With urinary
tract leakage, urea and creatinine quickly diffuse into extracellular fluid
including blood and the diminished excretion of urea and creatinine
causes the azotemia. Analytes that confirm that an azotemia is of postre­
nal origin are not available, Other abnormalities associated with de­
creased GFR (e.g., hypercalcemia, acidemia) may be present.

Urea/Creatinine Ratio

Ratio of serum urea (or serum UN) concentration to serum creati­

nine concentration is a calculated value reported with some serum
chemistry profile results. It has been proposed that urea/creatinine
ratios might help differentiate prerenal from renal azotemia, i.e., urea/
creatinine ratio will be higher in prerenal disorders than renal disorders.
Urea/creatinine ratios in dogs and cats, however, were not different
significantly in prerenal and renal azotemias when the degree of azote­
mia was considered, 43 Similar studies have not been performed for
horses. Until urea/creatinine ratios are shown to have diagnostic value
in horses, they should be interpreted with caution.
Other ratios using urea and creatinine have been used to attempt
to differentiate prerenal and renal azotemias such as urine urea/serum
urea ratios (urine to serum urea ratio), urine creatinine/serum creatinine
396 STOCKHAM

ratios (urine to serum creatinine ratio), and a ratio of (urine to serum

creatinine ratio) to (urine to serum urea ratio).55

Glucose

In mammals, stable plasma glucose concentrations represent an

equilibrium between biochemical pathways involving carbohydrates
(gluconeogenesis, glycogenolysis, glycolysis), hormonal interactions, and
dietary intake.

Hyperglycemia
Hyperglycemia can be caused by physiologic responses or patho­
logic states. Persistent hyperglycemia (diabetes mellitus) may be caused
by adenomas of the pars intermedia of the pituitary gland and the
resulting excess in cortisol or growth hormone/ 70- 81 iatrogenic hyper­
adrenocorticism,22 pheochromocytomas,138 and for undetermined rea­
sons.86· 107 A transient hyperglycemia may be found after eating (espe­
cially if consuming a high carbohydrate diet),32 after strenuous
exercise,47· 127 after prolonged halothane anesthesia,119 due to effects of
xylazine124· 137 or detomidine,51 during or shortly after intravenous glu­
cose administration, or be caused by endotoxemia.118

Hypoglycemia
Hypoglycemia can result from poor sample handling or may result
from pathologic states. Delayed separation of serum or plasma from
blood cells will allow time for blood cells (leukocytes, erythrocytes, and
platelets) to consume glucose and thus cause a falsely low glucose value
in the sample. Generally, rate of glucose consumption by cells is reported
to be 5% to 10% per hour but can be higher when a leukocytosis is
present. Pathologic causes of hypoglycemia in horses include hepatic
insufficiency,30 islet B-cell neoplasia, 104 hepatocellular carcinoma, 1°0 and
surreptitious injections of insulin.52 Slightly lower glucose concentrations
(but still within reference range) were reported after phenylbutazone
treatment.139

Total Protein, Albumin, Globulin, and

Albumin/Globulin Ratio

More than 1000 individual proteins have been characterized in

serum. Proteins other than albumin are collectively called globulins
or globulin. Serum globulin concentration is calculated by subtracting
measured albumin concentration from measured total protein concentra­
tion.
 INTERPRETATION OF EQUINE SERUM BIOCHEMICAL PROFILE RESULTS 397

Hyperproteinemia
Hyperproteinemia can be caused by hemoconcentration, inflamma­
tion, or B-lymphocyte neoplasia. Hemoconcentration can be caused by
either dehydration or shock and will produce higher concentrations of
both albumin and globulins (but maybe not enough to exceed reference
intervals). Clinical signs of dehydration or shock along with other evi­
dence of hemoconcentration (e.g., erythrocytosis) would support a con­
clusion of a hemoconcentration hyperproteinemia. Exercise and the
resulting loss of blood water can produce hyperproteinemia and hyper­
albuminemia.117
Depending on the duration and severity of an inflammatory disor­
der, the total protein, albumin, and globulin concentrations can remain
within reference intervals or change to a classic chronic inflammatory
dysproteinemia pattern, i.e., hyperproteinemia, hypoalbuminemia, hy­
perglobulinemia. Hypoalbuminemia results from decreased albumin
synthesis by hepatocytes induced by of inflammatory mediators; albu­
min is a negative acute-phase protein. Hyperglobulinemia results from
increased synthesis of certain globulins by hepatocytes (positive acute
or delayed phase proteins) and immunoglobulins by lymphocytes. His­
toric or current clinical signs of an inflammatory disease or an inflam­
matory leukocytosis would support a conclusion that a hyperprotein­
emia was caused by inflammation.
Neoplastic B-lymphocytes (such as in B-cell lymphosarcoma, plas­
macytoma, or myeloma) can result in overproduction of a specific immu­
noglobulin and produce a hyperproteinemia.60 A horse with such a
neoplasm may have a concurrent hypoalbuminemia for one or more
reasons (e.g., inflammation, renal, or enteric loss). Classifying such a
dysproteinemia requires locating neoplastic tissue and confirming the
diagnosis of a B-lymphocyte neoplasm through appropriate microscopic
or other methods.

Hypoproteinemia
Hypoproteinemia results from a variety of pathologic states that are
grouped into two major groups: (1) protein-losing disorders, and (2)
disorders causing decreased protein synthesis. Protein-losing disorders
include hemorrhage, protein-losing nephropathies, and protein-losing
enteropathies, and possibly protein-losing dermatopathies (rarely seen).
If the hemorrhagic disorder is severe enough to create an anemia,
then a concurrent hypoproteinemia (with lower albumin and globulin
concentrations) is expected.
In protein-losing nephropathies and enteropathies, a concurrent
hypoproteinemia and hypoalbuminemia are expected; however, there
may not be a hypoglobulinemia because of selective loss of smaller
proteins (albumin and some globulins) and retention of larger globulins.
If a glomerular disease (e.g., glomerulonephritis, amyloidosis) is causing
a hypoproteinemia or hypoalbuminemia, there will be a concurrent
398 STOCKHAM

proteinuria. Evidence of renal dysfunction (azotemia, dilute urine, elec­

trolyte abnormalities), however, will depend on the extent of renal
disease. If enteric disease is causing a hypoproteinemia, a horse should
have clinical evidence of such a disorder (malformed feces, diarrhea,
weight loss). To confirm enteric involvement, glucose or xylose absorp­
tion tests or intestinal biopsy usually are required.
A variety of disorders or situations that cause a decrease in protein
synthesis include hepatic insufficiency, maldigestion, malabsorption,
starvation, and the cachetic state of neoplasia. If these disorders cause a
hypoproteinemia, a concurrent hypoalbuminemia is expected. Globulin
concentrations also are expected to decrease but may not be enough
to cause a hypoglobulinemia. Concluding that one of the previously
mentioned disorders is causing a hypoproteinemia requires diagnostic
procedures or information specific for those disorders.
Lymphoid hypoplasia or aplasia can cause a hypogammaglobuli­
nemia, but that change by itself may not create a hypoproteinemia.

Albumin Concentrations
Albumin concentrations outside of reference intervals frequently
occur with hyperproteinemia or hypoproteinemia but not always.
Causes of hypoalbuminemia include the inflammatory disorders, pro­
tein-losing disorders, and disorders of decreased protein synthesis pre­
viously mentioned. Hyperalbuminemia usually is caused by hemo­
concentration but may result from two other causes. First, a common
analytic method for measuring serum albumin concentration is the bro­
mocresol green (BCG) dye binding method in which the BCG dye
preferentially binds to albumin more than other proteins. If the dye does
bind to globulins, however, then the measured albumin concentration
will show a false increase. Glucocorticoid hormones or compounds are
known to increase the synthesis of albumin and cause hyperalbumi­
nemia in humans, dogs, and cats; the same might be true for horses.

Albumin/Globulin Ratio
The albumin/globulin (A/G) ratio is reported with some chemistry
profiles. It is derived by dividing the measured albumin concentration
by the calculated globulin concentration. As with any calculated value,
changes in the A/G ratio will reflect changes in individual components
used for the calculation and thus may be of minimal extra value. A
decreased A/G ratio is expected with inflammatory disease, B-lympho­
cyte neoplasia, and in selective hypoproteinemias (such as protein-losing
nephropathies, some protein-losing enteropathies, some liver diseases).
A hyperproteinemia with a normal A/G ratio suggests hemoconcentra­
tion. A hypoproteinemia with a normal A/G ratio suggests disorders
such as hemorrhage, maldigestion, malabsorption, and starvation. An
increased A/G ratio is not common but suggests erroneous albumin
 INTERPRETATION OF EQUINE SERUM BIOCHEMICAL PROFILE RESULTS 399

measurement (see hyperalbuminemia above) or decreased synthesis of

gammaglobulins (lymphoid hypoplasia or aplasia).
Reference intervals for total protein, albumin, and globulin concen­
tration for foals are lower than those for mature horses; therefore, age­
specific reference intervals need to be used when interpreting serum
protein values. 10

Calcium

Calcium assays in routine biochemical profiles measure the total

calcium concentration. Of the total, approximately 40% is bound to
albumin; the remaining percentage is present as free ionized calcium or
complexed with anions such as citrate. Because of the high percentage
of albumin-bound calcium, serum calcium concentration should be inter­
preted with knowledge of a horse's serum albumin concentration. For
example, a horse with a mild hypocalcemia with a concurrent hypoal­
buminemia may not have a calcium metabolism disorder, just a dys­
proteinemia. It may be the case, however, that a horse with a "high
normal" serum calcium value and a concurrent hypoalbuminemia may
truly have a hypercalcemic metabolism disorder.

Hypercalcemia
Hypercalcemia in horses can be caused by renal insufficiency or
failure,18• 121• 122 pseudohyperparathyroidism, vitamin D toxicosis,85 and
ergocalciferol toxicosis. 66 Disorders that reduce GFR cause hypercalcemia
in horses because the kidneys are a major route of calcium excretion
in horses. With diminished renal excretion of calcium, hypercalcemia
develops. Also, kidneys are involved in both vitamin D and parathyroid
hormone metabolism. In one study of acute experimental renal disease,
increased concentrations of C-terminal parathyroid hormone and cal­
cium and lower concentrations of phosphorus were found. 37 Because
persistent hypercalcemia of any origin can lead to a hypercalcemic
nephropathy, it may be difficult to determine if renal disease is the
cause or the result of a hypercalcemia.
Pseudohyperparathyroidism is a paraendocrine disorder in which
neoplastic tissue produces a hypercalcemic-inducing substance. Neo­
plasms reported to cause this state in horses include gastric carcinoma,78
vulvar squamous cell carcinoma, 64 lymphosarcoma,40· 72• 73 adrenocortical
carcinoma,45 and ameloblastoma. 103

Hypocalcemia
Hypocalcemia can be caused by or associated with a hypoalbumi­
nemia, inadequate diet, lactation, cantharidiasis (blister beetle poison­
ing),94· 111 exercise,20• 112• 117 liver disease,108 and the effects of furosemide.46
Some authors refer to the hypocalcemia created by hypoalbumi-
400 STOCKHAM

nemia as a pseudohypocalcemia. In sera with hypoalbuminemia, there

may be a decreased total calcium concentration (thus the hypocalcemia
is real) but the physiologic control of ionized calcium concentration may
be normal. Formulas for adjusting the measured serum calcium have
been reported for dogs, but similar formulas have not been described
for horses. Also, because of assay variations, any formula derived from
one set of assays should be used cautiously if data for a patient were
obtained from other assay systems.
An imbalance of calcium and phosphorus in the diet can lead to a
hypocalcemia and secondary nutritional hyperparathyroidism. 63, 101 As­
sessing renal excretion of phosphorus may help establish the diagnosis
when physiologic processes have been able to maintain serum calcium
and phosphorus values within reference intervals.
Although not common, lactational hypocalcemia does occur in
mares. 97 The hypocalcemia develops when a mare is unable to replenish
the calcium lost in milk by mobilizing bone calcium or from diet.

Phosphorus
Assays that measure the serum phosphorus concentrations measure
the phosphorus present in inorganic phosphate molecules. Alterations
in serum phosphorus concentrations frequently are associated with other
biochemical data that are more specific for a pathologic state.

Hyperphosphatemia
Hyperphosphatemia is caused by or associated with poor sample
collection or handling and devitalized intestinal tissue. Because erythro­
cytes contain higher phosphorus concentrations than plasma, in vitro
hemolysis or delayed removal of serum from a clot can result in erron­
eously increased serum phosphorus concentrations. Serum and perito­
neal fluid phosphorus concentrations are higher (approximately 1-1.5
mg/dL) in horses with devitalized intestinal tissue. 5 Mild hyperphos­
phatemia also has been reported after endurance rides20 and can be
caused by diets with low calcium:phosphorus ratios.

Hypophosphatemia
Hypophosphatemia can be caused by increased loss or decreased
intake of phosphorus. Horses are unique in that renal disease leads to
hypophosphatemia. 12 Glucose infusions can induce a hypophosphatemia
in horses, 105 and hypophosphatemia was found after prolonged halo­
thane anesthesia. 119

Magnesium
Magnesium occasionally is part of an equine biochemical profile.
Relatively little is known about disorders that alter serum magnesium
 INTERPRETATION OF EQUINE SERUM BIOCHEMICAL PROFILE RESULTS 401

concentrations; thus, interpretation of results are difficult. Hypomagne­

semia is a major manifestation of cantharidiasis (blister beetle poison­
ing). 111 Slight decreases in magnesium concentrations were found after
endurance rides. 2° Concentrations of magnesium in equine erythrocytes
are approximately four times serum values and thus in vitro hemolysis
· could cause minor increases in measured values. 80

Iron

In nearly all samples, a serum iron concentration is that quantity of

iron that is present in serum and bound to transferrin, a transport
protein. Hypoferremia can be due to two pathologic states: inflammation
and iron deficiency. Inflammatory disorders initiate a change in iron
metabolism that produces hypoferremia, hyperferritinemia, and in­
creased iron storage; the hypoferremia has been referred to as pseudo­
iron deficiency. 1 1 3• 1 1 4 Other evidence of inflammatory disease (e.g.,
historic, physical, neutrophilia, hyperproteinemia) would support the
conclusion of inflammatory hypoferremia, Iron-deficiency states are un­
common in horses, but they might occur with chronic external blood
loss. Foals have lower serum iron concentrations than mature horses. 65
Hyperferremia has been reported in cases of iron toxicity35• 83 and in
hospitalized horses114 because of excessive iron supplementation. Exoge­
nous corticosteroids have induced hyperferremia in horses. 115

Bilirubin (Total and Fractions)

Common assays that measure serum bilirubin concentrations can

be separated into two categories: spectrophotometric assays and the dry­
reagent methods. In more traditional spectrophotometric assays, a total
bilirubin concentration is determined by an assay that is designed to
measure all bilirubin fractions. Then, another bilirubin assay measures
the direct bilirubin concentration that represents the sum of bilirubin
fractions (conjugated bilirubins and o-bilirubin). The indirect bilirubin
concentration (or unconjugated bilirubin) is derived by subtraction (total
minus direct).
Using thin-layering techniques, a dry-reagent system was developed
that allowed measurement of different bilirubin fractions. 1 33 The total
bilirubin assay still measures all bilirubin fractions. Another assay sys­
tem measures the unconjugated bilirubin concentration and the
conjugated bilirubin (monoglucuronide and diglucuronide) concentra­
tion.136 A o-bilirubin fraction is calculated by subtracting the conjugated
and unconjugated fractions from the total bilirubin concentration. A
direct bilirubin concentration can be calculated by adding the concentra­
tions of the conjugated fractions and o-bilirubin. The measured
unconjugated fraction also can be called the indirect bilirubin concentra­
tion to be consistent with spectrophotometric assay systems.
402 STOCKHAM

There are three major reasons for understanding the different types
of assay systems. First, laboratories may report bilirubin concentrations
using different terms because of the different assays. Second, the total
bilirubin concentration measured by the dry-reagent system can give a
false low result in horse serum because of an unidentified inhibitor of
the reagent system. This problem is identified when the sum of the
conjugated and unconjugated bilirubin assays exceed the value deter­
mined by the total bilirubin assay. Third, equine hepatocytes conjugate
bilirubin with glucose more than with glucuronic acid.24 Assays designed
to measure the glucuronide conjugates may not accurately measure the
equine bilirubin fractions conjugated with glucose.
Hyperbilirubinemia in horses, like other mammals, is caused by
pathologic states in which the rate of bilirubin formation exceeds excre­
tion. But unlike other domestic mammals, anorexia causes the develop­
ment of hyperbilirubinemia in horses. In this state, the increased
unconjugated bilirubin fraction results from the decreased uptake or
conjugation of bilirubin. An exact mechanism for the unique physiologic
variation still has not been determined with certainty.38
In vivo hemolysis, either extravascular or intravascular, will lead to
increased bilirubin formation and thus may cause a hemolytic hyperbili­
rubinemia. The degree of hyperbilirubinemia will vary with severity
and duration of hemolysis. A concurrent finding of anemia, especially
with macrocytosis, and unconjugated hyperbilirubinemia would support
a conclusion of a hemolytic icterus. Causes of a hemolytic anemia in­
clude neonatal isoerythrolysis, idiopathic immune-mediated hemolytic
anemia, equine infectious anemia, babesiosis, red maple leaf toxicosis,
and glucose-6-phosphate dehydrogenase deficiency. Large doses of hep­
arin can lead to increased extravascular hemolysis and minor increases
in serum bilirubin concentrations.39
Hepatic necrosis and cholestasis (impaired bile flow) within the
liver or through major bile ducts can cause a hyperbilirubinemia. These
icteric states are classified as either hepatic (or intrahepatic) or posthe­
patic (or extrahepatic) icterus. In contrast with other domestic mammals,
the unconjugated bilirubin fraction may dominate early in horses with
cholestatic icterus and can represent 50% of the total concentration by 3
to 5 days after experimental duct ligations.23 Also, experimental hepatic
necrosis causes a hyperbilirubinemia dominated by unconjugated biliru­
bin.23 Direct bilirubin concentrations, however, can be the predominant
component of increased bilirubin concentrations in horses with ligated
bile ducts.11 With time, the concentration of o-bilirubin will increase in
cholestatic disorders. Besides progressive and frequently idiopathic liver
disease, causes of cholestasis include blockage of the common hepatic
duct88 and cholelithiasis. 125 Hyperbilirubinemia (unconjugated) can de­
velop a few days after prolonged halothane anesthesia.119 A persistent
hyperbilirubinemia found in an otherwise healthy horse was thought to
be the result of defective conjugation process.33
Other laboratory evidence of a cholestatic process will vary with
the cause of the cholestasis. Typically, serum hepatic enzymes will be
 INTERPRETATION OF EQUINE SERUM BIOCHEMICAL PROFILE RESULTS 403

increased reflecting either the cholestatic process or damaged hepato­

cytes. Evidence of hepatocellular dysfunction (hypoalbuminemia, lower
urea concentration, hypoglycemia) would be expected with the more
severe chronic liver disorders.

Cholesterol and Triglyceride

Routine cholesterol and triglyceride assays measure total cholesterol

and total triglyceride concentrations, respectively. Cholesterol and tri­
glyceride molecules circulate in lipoprotein particles that are produced
by hepatocytes or intestinal mucosal cells and modified by peripheral
lipid metabolism.
Major concerns regarding cholesterol and triglyceride concentra­
tions of horses and ponies are in the hyperlipemia disorders. Hyperli­
pemia represents a lipid metabolism disorder that is associated with
or precipitated by several conditions including malnutrition, obesity,
anorexia, stress, pregnancy, or lactation. 61• 13?· 13 1 Through one or more
mechanisms, the liver overproduces very low density lipoproteins
(VLDL) that are triglyceride-rich molecules. 129 Serum triglycerides con­
centrations start to increase within 3 days of fasting in horses. 8

SERUM ELECTROLYTES

Sodium

Serum sodium concentrations reflect a ratio of the total body sodium

content to total body water content; therefore, interpretation of serum
sodium concentrations is aided greatly by knowing the hydration status
of a horse. Hyponatremia in a dehydrated horse indicates that the
horse has lost hypertonic fluids (or relatively more sodium than water).
Hypernatremia in a dehydrated horse would indicate that the horse has
lost hypotonic fluids (solute-free water) or has been deprived of water.

Hyponatremia
Hyponatremia associated with dehydration or hypovolemia indi­
cates that a horse has been depleted of sodium. Major routes of sodium
depletion are through kidneys (generalized renal disease, renal tubular
disease, furosemide, 132 osmotic diuresis,1°5 ) intestines (diarrhea or seques­
tration of sodium-rich fluids),28• 67 or sweat. 102 Hyponatremia also can
occur with uroperitoneum. 13· 126 Hyponatremia in edematous horses
would indicate that the horse is retaining relatively more water than
sodium and suggests disorders such as congestive heart failure, hepatic
failure, and protein-losing nephropathies.
404 STOCKHAM

Normonatremia
Normonatremia may be a significant finding in either a dehydrated
or edematous horse. Normonatremia in a dehydrated horse indicates
that the horse has lost isotonic fluid (probably via kidneys or intestines)
and therapy should include replacement of not only water but sodium.
In an edematous horse, normonatremia would indicate that the horse
has not only excess total body water content but also increased total
body sodium content.

Hypernatremia
Hypernatremia occurs primarily when there has been decreased
water intake or increased loss of hypotonic fluids (loss through respira­
tions, central or renal diabetes insipidus). 109· 116 Hypernatremia has been
found in horses within 30 minutes of strenuous exercise. 22 Also, because
of the relatively narrow sodium reference interval, evaporation of serum
(by allowing serum exposure to room air) can increase the sodium
concentration sufficiently in a sample to cause an erroneous hyperna­
tremia.

Potassium

Serum potassium (K) concentrations depend on the total body K

content and the acid-base status of the animal; however, total body K
content may decrease in a horse before a hypokalemia develops. 62 Also,
experimentally-induced acidemias caused only slight changes in serum
K concentrations. 54
Hyperkalemia is primarily caused by decreased renal excretion
(anuric or oliguric disorders with an abrupt decrease in GFR, uro­
peritoneum 13· 126) or a shift of K from intracellular to extracellular fluid
(promoted by acidemia). In hyperkalemic periodic paralysis, the hyper­
kalemia is caused by an abnormal muscle sodium (Na) channel. 106 Stren­
uous exercise causes a transient hyperkalemia that is thought to be
caused by the release of K from muscle fibers. 47· 57· 74· 127 Because of the
relatively high K content of equine erythrocytes,87 in vitro hemolysis or
delayed removal of serum from a clot can result in increased measured
K values. Pseudohyperkalemia will probably occur in a horse with
marked thrombocytosis.
Hypokalemia is primarily caused by disorders that cause loss of K
from the body (via kidneys, intestines, or skin) or through a shift of K
from extracellular to intracellular fluid (promoted by alkalemia). Furose­
mide treatments can lead to the rapid development of hypokalemia,
possibly due to a shift of potassium into intracellular fluid caused by
the furosemide-induced alkalosis46· 132 and through increased fecal loss
of K. 3 Equine sweat has a high K content and thus sweating can lead to
hypokalemia. 20· 102 Diarrhea and intestinal obstructions can cause in-
 INTERPRETATION OF EQUINE SERUM BIOCHEMICAL PROFILE RESULTS 405

creased K loss and hypokalemia.28 Hypokalemia due to a dietary defi­

ciency is unlikely because typical equine diets are high in K.

Sodium/Potassium

The sodium/potassium (Na/K) ratio is determined by dividing the

Na concentration by the K concentration. A low Na/K ratio can be seen
in hyponatremic or hyperkalemic horses due to a variety of disorders
and thus has very little diagnostic importance in horses.

Chloride

Because serum must remain electrically neutral, abnormal serum

chloride concentrations tend to follow patterns. Hypochloremia is associ­
ated with hyponatremia, increased bicarbonate concentrations, or an
increased anion gap. Hyperchloremia is associated with hypernatremia
or decreased serum bicarbonate concentrations. Accordingly, the cause
of abnormal chloride concentrations usually can be found by pursuing
the cause of the abnormal concentrations of Na, bicarbonate, or unmeas­
ured anions. Furosemide treatments can lead to hypochloremia through
increased renal excretion of chloride.46 Because of the relatively large
quantity of chloride in equine sweat compared with Na content,
sweating may cause a more pronounced hypochloremia than hypona­
tremia.20, 102 Slight decreases in serum chloride concentrations after stren­
ous exercise also might be associated with lactic acidosis.22• 27

Total Carbon Dioxide Content

Total carbon dioxide content (tCO2 or sometimes just CO2 ) may be

one of the "electrolytes" measured in serum profile assays. The tCO2
represents the total quantity of CO2 that can be liberated from serum. In
nearly all sera, approximately 95% of the tCO2 comes from bicarbonate.
Thus, tCO2 is really a method of estimating bicarbonate concentration
in serum. Lower bicarbonate concentrations may be the result of the
consumption of buffers during an acidotic state (such as lactic acidosis),
through bicarbonate loss via kidneys (as a compensation for a respira­
tory alkalosis or as the result of renal tubular disease), or intestinal loss
(diarrheas).28 Delayed analysis of blood samples6 or exposure of blood or
serum to room air will lead to lower tCO2 values. Increased bicarbonate
concentrations (and thus tCO2 values) due to pathologic states are un­
common in horses, but they can be associated with metabolic alkalosis
or renal compensation for a respiratory acidosis. Parenteral administra­
tion of sodium bicarbonate solutions for either therapeutic or potential
performance reasons will cause increased tCO2 values.6
406 STOCKHAM

Anion Gap

An anion gap value is reported with some biochemical profile

results and represents the following calculation: ([Na] + [K]) - ([chlo­
ride] + [bicarbonate]). If a chemistry system is not designed to directly
measure bicarbonate concentrations, then the tCO2 value is used as a
substitute for the bicarbonate concentration. An increased anion gap
indicates increased concentration of an anion other than chloride or
bicarbonate, or increased concentration of an unmeasured anion. The
unmeasured anion could be lactate, ketone bodies (acetoacetate, �-hy­
droxybutyrate), anions from other organic acids, or perhaps a foreign
substance. In horses with abdominal pain, higher anion gap values
correlate with a poorer prognosis.17 A decreased anion gap does not
have diagnostic significance in equine samples.

Calculated Osmolality

Some laboratories report serum "osmolality" with other profile

results. Unless otherwise specified, the reported osmolality usually is
calculated using one of several formulas. The more common osmolality
formulas were derived for human sera but are frequently used for
domestic mammal sera. These formulas include 1) calculated osmolality
= 2 [Na]; 2) calculated osmolality = 2 [Na] + BUN/3 + glucose/20;
3) calculated osmolality = 1.86 (Na + K) + BUN/2.8 + glucose/18.
Major points to remember are that the reported osmolality usually is a
calculated value, the calculated value depends on analyte concentrations
and formulas used to calculate it, and the calculated value may be
markedly different from the true serum osmolality (because of a solute
other than urea, glucose, or sodium).

SERUM ENZYMES

AST/GOT and LD/LDH

Serum aspartate transaminase (AST) (formerly called glutamate oxa­

loacetate transaminase [GOT]) activity and lactate dehydrogenase (LD)
activity have similar diagnostic value in horses. The major reason for
including AST or LD in an equine biochemical profile is to attempt to
detect hepatocellular disease. Neither AST nor LD (or any other enzymes
in this chapter) assess liver function and thus should not be called liver
function tests. Major tissue sources of increased serum AST and LD
activities are hepatocytes and muscle fibers (skeletal or cardiac). A
variety of pathologic states (e.g., hypoxia, cirrhosis, necrosis, neoplasia,
lipidosis,84, 1 34 infections, 1 23 carbon tetrachloride toxicosis,15 iron toxicosis,
Senecio toxicosis,69 trauma, associated with tetanus antitoxin,76 exertional
rhabdomyolysis128 ) can damage hepatocytes or muscle fibers sufficiently
 INTERPRETATION OF EQUINE SERUM BIOCHEMICAL PROFILE RESULTS 407

to allow escape of enzymes from cells. Horses may have increased AST
and LD values due to postanesthetic myopathy or hepatic injury. 1 19
Cellular damage can result in necrosis (irreversible damage) or can be
reversible. The process by which enzymes escape from the cytosol of
cells in the absence of necrosis is not firmly established, but may be
through formation of membrane blebs. 53 The degree by which AST or
LD is increased somewhat suggests the degree of cell damage, but there
is not a strong correlation because other factors also influence changes.
Nonpathologic states also may cause increased AST and LD. Exer­
cise and intramuscular injections allow release of sufficient muscle en­
zymes to increase serum AST and LD values. Last, because erythrocytes
contain AST and LD, in vitro hemolysis or delayed removal of serum
from a clot can give false increased serum values of these enzymes.

ALT/GPT
Serum ALT (formerly called glutamate pyruvate transaminase
[GPT]) activity may be part of a serum biochemical profile, but it has
very little diagnostic value for horses. Hepatocellular disease may cause
increased serum ALT values, but such increases are not always present
in horses with hepatocellular damage.

ALP and GGT/GGTP

Alkaline phosphatase (ALP) and -y-glutamyltransferase (GGT) (also
called -y-glutamyltranspeptidase [GGTP]) usually are included in bio­
chemical profiles because serum activities of the enzymes increase when
mammals have cholestatic disorders. Both ALP and GGT are associated
predominately with cell membranes of hepatocytes and biliary epithelial
cells. In the presence of cholestasis, there is an increased production and
release of ALP from hepatocyte membranes (possibly mediated through
action of bile salts). Cholestasis is also thought to increase GGT produc­
tion, but the mechanism is not understood. Hepatocyte necrosis also
might cause increased serum GGT values. 135 In clinical and experimental
disease, GGT has been shown to be a better indicator of cholestasis or
hepatobiliary disease in horses than ALP 1· 58 and has been found to be
increased in a variety of disorders including cirrhosis and hemochro­
matosis,93 amyloidosis, kleingrass-associated hepatotoxicosis,25 and cho­
lelithiasis. 125
Other tissue sources of GGT in horses include pancreas and kid­
neys. 98 However, because pancreatic disease is very uncommon in horses
and because renal disease does not contribute to increased serum GGT
activity, serum GGT activity is relatively specific for biliary or cholestatic
disease, Damage to renal tubular cells causes increased urinary excretion
of GGT.
ALP represents a family of phosphatases with optimal activity in
an alkaline environment; thus, there are many potential tissue sources
408 STOCKHAM

of ALP. 34, 48 Besides hepatobiliary membrane ongm, other tissues that

might contribute to increased serum ALP values include bone, intestine,
and placenta. Young and growing horses have higher serum ALP values
than mature horses, and the higher activity is attributed to bone ALP
isoenzyme. 56· 68 Neonatal foals also have higher serum GGT values than
their mares. 92 Horses with colic resulting from intestinal disorders did
have increased ALP values in peritoneal fluid but not increased serum
values; the source of the increased ALP activity in one clinical study
was granulocytes. 49 In an experimental study, intestine was considered
the source. 29 Equine placentas have high ALP activity, but the serum
ALP values for horses did not differ significantly during pregnancy. 77, 90

Creatine Kinase
Creatine kinase (CK) (also called creatine phosphokinase [CPK]) is
included in biochemical profiles because it has high specificity for dam­
aged muscle. The major tissue sources of serum CK are skeletal, cardiac,
and smooth muscle fibers, 50 High quantities of CK also are present in
central nervous system tissues. Damage to those tissues does not cause
increased serum CK, but it may increase CK activity in cerebrospinal
fluid. Like the other cytosolic enzymes, CK released from cells may
be the result of necrosis or reversible cell damage. Pathologic states or
other situations that may produce increased CK values in serum include
exertional myopathy, 127, 128 postanesthetic myopathy,119, 120 succinylcholine
administration, 1 4 prolonged recumbency, trauma, intramuscular injec­
tions,75 strenuous exercise, and cardiac disease. 26 Mildly increased CK
values also have been reported in horses that have had intestinal disease;
at least part of the increase was attributed to the MB isoenzyme in
smooth muscle. 50
Sometimes a CK value within a reference interval greatly aids data
interpretation. For example, increased serum values for AST or LD
found concurrently with normal CK activity suggest that the AST or LD
values are increased because of hepatocellular disease and not muscle
damage. Such conclusions, however, should be made cautiously because
the circulating half-life of CK is shorter than both AST and LD.
Poor sample collection and handling also can result in an increased
measured CK value. One group of authors proposed that poor venipunc­
ture technique would allow CK from surrounding muscle fibers to
contaminate a sample. 4 1 Also, in vitro hemolysis or delayed removal of
serum from a clot may produce a false elevation in CK values because
erythrocytes contain substances (i.e., adenylate kinase, glucose-6-phos­
phate) that interfere with some CK assays.

Amylase and Lipase

Amylase (AMS) and lipase (LPS) may be included in a biochemical
profile. AMS and LPS activity have not been shown to be of any
diagnostic value in horses.
 INTERPRETATION OF EQUINE SERUM BIOCHEMICAL PROFILE RESULTS 409

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Steven L. Stockham, DVM
A336 Clydesdale Hall
University of Missouri-Columbia
Columbia, MO 652 1 1