Increased Blood Urea Nitrogen
Problem Definition and Recognition
Identified by finding blood urea nitrogen (BUN) concentration greater than the reference interval. Markedly increased concentrations of urea may manifest as signs of uremia including vomiting, anorexia, GI bleeding, and lingual ulcers.
Pathophysiology
Urea is formed by hepatic conversion of ammonia (originating from intestinal protein catabolism) via the urea cycle. Urea is cleared primarily by glomerular filtration.
Increased concentrations of BUN can result from increased production (diets high in protein, gastrointestinal hemorrhage with subsequent digestion of plasma proteins) or decreased renal clearance. Decreased renal clearance may be due to reduced renal blood flow (prerenal azotemia), intrinsic renal disease (renal azotemia), or urinary tract obstruction/rupture (postrenal azotemia). In urinary tract rupture, urea released into the peritoneal cavity is reabsorbed.
Initial Diagnostic Plan
Increased urea synthesis is suspected when a patient has an increased BUN but normal creatinine concentration. Confirmation rests on review of the diet and evaluation for evidence of GI hemorrhage (melena, hemorrhagic anemia; see Chapter 54) or recognition of predisposing factors for same (severe thrombocytopenia).
Reduced renal clearance typically manifests as increased concentrations of both urea and creatinine. Postrenal causes must be identified by clinical signs of urinary tract obstruction (large distended bladder, inability to void) or rupture (ascites). Urinary tract rupture can be confirmed by identifying creatinine concentration in the peritoneal fluid greater than that of serum or sonographic confirmation of the rupture. Once postrenal azotemia is excluded, differentiation of prerenal from renal azotemia can generally be accomplished by evaluating urine specific gravity as a measure of renal concentrating ability and response to fluid diuresis. Concentrating ability (increased specific gravity) is retained in prerenal azotemia, but typically is lost or decreased with renal azotemia.
Decreased Blood Urea Nitrogen
Problem Definition and Recognition
Identified as BUN concentration less than reference interval. Decreased urea levels are generally not associated with significant clinical signs.
Pathophysiology
Reduced BUN may result from decreased production due to markedly restricted dietary protein or liver failure, resulting in lack of hepatic conversion of ammonia to urea. Increased renal loss may result from chronic polyuric conditions or therapeutic dieresis.
Initial Diagnostic Plan
History should be reviewed concerning diet and possibility of polyuria. Decreased BUN resulting from hepatic failure is usually obvious by review of results of liver enzyme and bilirubin concentration or results other liver function tests.
Increased Creatinine
Problem Definition and Recognition
Identified as creatinine level greater than reference interval. Increased serum creatinine may result in signs of uremia as with BUN.
Pathophysiology
Serum creatinine comes from the spontaneous nonenzymatic degradation of muscle creatine. Rate of formation is constant and proportional to lean muscle mass. Creatinine clearance is dependent on glomerular filtration as for BUN.
Initial Diagnostic Plan
See “Initial Diagnostic Plan” under section “Increased Blood Urea Nitrogen.”
Decreased Serum Creatinine
Problem Definition and Recognition
Concentration of serum creatinine below the reference interval. Reduced concentration of creatinine is not associated with significant clinical signs.
Pathophysiology
Reduced concentrations of serum creatinine can result from either decreased production due to reduced muscle mass or increased loss from polyuric states.
Initial Diagnostic Plan
Reductions in serum creatinine are not clinically significant or generally diagnostically useful.
Hyperalbuminemia
Problem Definition and Recognition
Identified as serum albumin concentration above the reference interval. Increased albumin does not cause clinical signs per se.
Pathophysiology
Albumin is produced by the liver and serum concentration reflects a balance between the rate of production and normal protein catabolism. Albumin acts as a negative acute-phase reactant, production being decreased with acute inflammation. Accelerated loss can be seen in a number of conditions (see section “Hypoalbuminemia”). Apart from albumin homeostasis, serum albumin concentration will be affected by hydration status.
Initial Diagnostic Plan
The main recognized cause of significantly increased albumin concentration is dehydration.
Hypoalbuminemia
Problem Definition and Recognition
Identified as serum albumin concentration below reference intervals. Animals may show signs of edema or body cavity effusions due to lack of colloid osmotic pressure normally supplied by albumin.
Pathophysiology
Causes of reduced serum albumin concentration can be classified as (1) reduced production, (2) increased loss, (3) third-space loss (sequestration), or (4) dilution. Specific causes are listed in Table 55-1.
Initial Diagnostic Plan
Many specific causes may be obvious from clinical signs or results of minimum database (hemorrhage, hepatic insufficiency, peritonitis). When hypoalbuminemia is present in an animal with no obvious clinical conditions, urine should be examined for protein to rule out renal loss. Gastrointestinal loss is a common cause of hypoalbuminemia without obvious physical findings or abnormalities of routine laboratory tests other than the protein abnormalities.
TABLE 55-1. Common causes of hypoalbuminemia
| Mechanism | Specific Causes |
| Decreased production | Hepatic insufficiency* |
| Starvation | |
| Sepsis, inflammation* | |
| Secondary to marked hyperglobulinemia | |
| Increased loss | Hemorrhage |
| Gastrointestinal loss | |
| Glomerular loss* | |
| Sequestration (“third spacing”) | Inflammatory body cavity effusion |
| Interstitial fluid accumulation from increased vascular permeability | |
| Dilutional | Fluid therapy |
*Typically affects only albumin (not globulins).
Hyperglobulinemia
Problem Definition and Recognition
Identified as a globulin concentration greater than reference interval. Marked hyperglobulinemia may cause clinical signs related to hyperviscosity. In addition, hemorrhage may occur due to impaired platelet function.
Pathophysiology
Globulins consist of immunoglobulins produced by lymphocytes and a variety of acute-phase proteins produced by the liver. Marked increases in serum globulins are typically the result of immunoglobulin production. Broadly, hyperglobulinemia can be thought of as the result of (1) increased acute-phase protein or immunoglobulin production in acute and chronic inflammatory conditions, respectively, or (2) neoplastic production of immunoglobulins by lymphoma or plasma cell tumors.
Initial Diagnostic Plan
Mild increases in globulins are generally the result of acute or chronic inflammation and further diagnostics are generally not pursued. In cases of marked hyperglobulinemia, serum protein electrophoresis may be useful in differentiating lymphoid neoplasia from chronic immune stimulation.
Hypoglobulinemia
Problem Definition and Recognition
Identified as a globulin concentration less than the reference interval.
Pathophysiology
Hypoglobulinemia is generally the result of decreased immunoglobulins since reduced hepatic production of acute-phase reactants (alpha and beta globulins) is often not sufficient to reduce globulins below reference intervals if immunoglobulin concentrations are normal. Other than in neonatal animals, hypoglobulinemia is typically the result of whole plasma loss (lost along with albumin loss, see Table 55-1).
Initial Diagnostic Plan
Globulin levels are normally lower in neonates than in adults, and so may be below reference intervals. Otherwise, considerations are the same as for causes of whole plasma loss in hypoalbuminemia (see Table 55-1).
Increased Serum Alanine Aminotransferase
Problem Definition
An increased serum alanine aminotransferase (ALT) activity is defined as an activity greater than the species reference interval for the specific laboratory and methodology used. When describing or comparing increased serum enzyme activities, it is useful to think in terms of the fold increase above the upper reference limit (URL).
Pathophysiology
ALT is a cytoplasmic enzyme present at highest concentrations in hepatocytes. ALT (and aspartate aminotransferase, AST) is considered a “leakage” enzyme whose serum activity can increase following cell injury or cell death. Although serum ALT activity is acutely proportional to the number of cells injured, the magnitude of the increase does not distinguish between sublethal damage and necrosis. ALT may also be released from hepatocytes during regeneration. Importantly, increases in leakage enzymes (ALT and AST) provide no information about liver function. Serum ALT activity can be within reference intervals in spite of severe hepatic dysfunction or hepatic failure. Mild increases in ALT activity have been associated with glucocorticoid and anticonvulsant drug administration in dogs.
Although often referred to as “liver specific” in dogs and cats, ALT is also present in lower concentrations in skeletal and cardiac muscle. Serum ALT activity can increase following severe muscle injury, but such increases are generally mild compared to increases in creatine kinase (CK) activity (see section “Increased Serum Creatine Kinase”).
Initial Diagnostic Plan
Serum ALT activity should be interpreted in conjunction with clinical signs as well as other serum enzymes and indicators of hepatic function on the biochemical profile. A wide variety of pathologic processes can cause increased serum ALT activity, including processes that are not primary liver diseases (Table 55-2). Rechecking ALT activity after several days to weeks is often useful to determine if an acute hepatic insult is resolving; more chronic inflammatory liver diseases may result in periodic “flares” of ALT activity increases. Hepatic biopsy may be required for specific diagnosis.
TABLE 55-2. Conditions causing increased serum ALT and AST activity
| Category | Underlying Disorders |
| Metabolic | Hepatic lipidosis, diabetes mellitus, feline hyperthyroidism, amyloidosis, canine hyperadrenocorticism (typically mild) |
| Neoplastic | Lymphoma, hepatocellular carcinoma, metastatic neoplasia, histiocytic sarcoma, and others |
| Inflammatory | Leptospirosis, infectious canine hepatitis, cholangitis/cholangiohepatitis, feline infectious peritonitis, chronic hepatitis (idiopathic, copper, drug induced), cirrhosis, pancreatitis, inflammatory bowel disease |
| Hypoxic Toxic | Shock, acute blood loss, congestive heart failure Acetaminophen, anesthetics, NSAIDs, many antibiotics/antifungals, methimazole, and others |
| Drugs (dogs) Miscellaneous | Corticosteroids, anticonvulsants Portosystemic shunt, lysosomal storage diseases, parasitic hepatic migration |
| Muscle | Muscle necrosis or trauma, myopathy/myositis (primarily affect AST), muscular dystrophy |
Decreased Serum Alanine Aminotransferase
A serum ALT activity below the species reference interval is not considered clinically significant.
Increased Serum Alkaline Phosphatase
Problem Definition
An increased serum alkaline phosphatase (ALP) activity is defined as an activity greater than the species reference interval for the specific laboratory and methodology used. When describing or comparing increased serum enzyme activities, it is useful to think in terms of the fold increase above the URL.
Because most reference intervals are for adult animals, it is important to keep in mind the effect of age on serum ALP activity. Neonatal puppies and kittens have transient marked ALP increases due to colostrum ingestion. Young animals with actively growing bones will have increased serum activity of the bone ALP isoform, causing their serum ALP activity to be greater than the reference intervals for normal adult animals (typically <4–5× URL).
Pathophysiology
ALP is an enzyme that is attached to cell membranes. By contrast to the “leakage” enzymes ALT and AST, ALP (and gamma glutamyltransferase, GGT) is considered an “induced” enzyme whose serum activity increases following increased cellular production. Increased cellular enzyme production may take several days to result in increased serum activity. Three different ALP isoforms are recognized (liver or LALP, bone or BALP, and corticosteroid induced or CALP) and can be identified by specialized laboratory tests. ALP in the liver is associated with biliary epithelial cells and canalicular membranes of hepatocytes. Increased ALP production resulting in increased serum ALP activity occurs with cholestasis, certain drugs (in dogs only), increased osteoblastic activity, and a variety of chronic diseases.
TABLE 55-3. Common causes of increased serum ALP activity
| Category | Underlying Disorders |
| *Drug induction (dogs) | Corticosteroids—exogenous (oral, parenteral, ophthalmic, otic, topical) or endogenous (hyperadrenocorticism), anticonvulsants |
| *Cholestasis | Any hepatic or posthepatic cause of impaired bile flow (e.g., hepatocyte swelling, hepatitis, pancreatitis, cholangitis, bile duct obstruction, and hepatic/biliary neoplasia) |
| Osteoblastic activity | Young age (growing bones), osteosarcoma, other bone neoplasia, healing fracture |
| Endocrine | Hyperadrenocorticism (steroid induction, dogs), diabetes mellitus, feline hyperthyroidism, canine hypothyroidism, and hyperparathyroidism |
| Other | Colostrum ingestion, mammary gland neoplasia, breed related (Siberian husky, Scottish terrier). |
*Often causes marked increases in ALP activity (>10× URL).
Cholestatic diseases result in marked serum ALP activity increases in dogs (>10× URL) but less marked increases in cats. The half-life of LALP is about 3 days in dogs but only 6 hours in cats, and cats have less ALP concentration per gram of liver tissue, resulting in a relatively smaller magnitude of serum ALP activity increases in cats with cholestatic liver disease compared to dogs.
Drug induction can result in marked serum ALP activity increases in dogs only. Corticosteroids, endogenous or exogenous in any form, can cause increases more than 20 times URL. Anticonvulsants generally cause milder increases (<10× URL). Although CALP activity can be specifically measured, the utility of doing so is uncertain since the initial rise in serum ALP activity in dogs receiving corticosteroids is due to LALP, with CALP increasing later. In addition, there is considerable individual variation and chronic stress due to a variety of diseases can also induce CALP production.
Increased osteoblastic activity can result in relatively mild increases in ALP activity due to production of BALP. This is commonly seen in young animals with growing bones, and may also occur with osteosarcoma, other bone neoplasms, and fracture healing.
Additional causes for increased serum ALP activity are listed in Table 55-3. Serum ALP activity gives no information about liver function.
Initial Diagnostic Plan
Serum ALP activity should be interpreted in conjunction with clinical signs as well as other serum enzymes and indicators of hepatic function on the biochemical profile. In dogs with cholestasis, serum ALP activity often increases prior to increases in serum bilirubin concentration. In dogs, careful consideration should be given to potential ALP induction by drugs (corticosteroids in any form, or anticonvulsants) or secondary to hyperadrenocorticism. These dogs will generally have normal total bilirubin and hepatic function tests and remain clinically healthy, unless a toxic hepatopathy develops. Increased serum CALP activity is sensitive but not specific for hyperadrenocorticism in dogs. In cats, mild increases in ALP activity (2–3× URL) can indicate significant cholestasis. Cats with primary hepatic lipidosis may have increased ALP activity with normal GGT activity.
Decreased Serum Alkaline Phosphatase
A serum ALP activity below the species reference interval is not considered clinically important.
Increased Serum Aspartate Aminotransferase
Problem Definition
An increased serum AST activity is defined as an activity greater than the species reference interval for the specific laboratory and methodology used. When describing or comparing increased serum enzyme activities, it is useful to think in terms of the fold increase above the URL.
Pathophysiology
AST is a “leakage” enzyme present in the cytoplasm and mitochondria of hepatocytes and muscle cells. Similar to ALT, increases in serum AST activity can result from either cell injury or cell death. Serum AST activity increases due to the same types of liver diseases as described for ALT (see Table 55-2), but the magnitude of the increase often less than for ALT and AST activity may normalize faster than ALT activity after an acute liver insult. AST is less liver specific than ALT, with serum activity increasing whenever muscle injury occurs. Mild increases in AST activity have been reported in dogs receiving corticosteroid or anticon-vulsant therapy. AST is also contained within erythrocytes, so in vitro hemolysis can cause artifactual increases. As with ALT, AST activity gives no information about liver function.
Initial Diagnostic Plan
As described for ALT, serum AST activity should be interpreted in conjunction with clinical signs as well as other serum enzymes and indicators of hepatic function on the biochemical profile. Measurement of the muscle-specific enzyme, CK, may help determine if an increased AST activity is due to muscle injury; however, CK has a shorter half-life and will normalize faster than AST. Serial determinations of AST activity are useful for following resolution of hepatic disease.
Decreased Serum Aspartate Aminotransferase
A serum AST activity below the species reference interval is not considered clinically significant.
Increased Serum Creatine Kinase
Problem Definition
An increased serum CK activity is defined as an activity greater than the species reference interval for the specific laboratory and methodology used. When describing or comparing increased serum enzyme activities, it is useful to think in terms of the fold increase above the URL.
TABLE 55-4. Common causes of increased serum CK activity
| Category | Underlying Disorders |
| General | Intramuscular injections, surgery, traumatic venipuncture, anorexia in cats, strenuous exercise, seizures, muscle trauma, ischemia, or necrosis from any cause |
| Endocrine |
