LIVER ENZYMES

consultant on call

Interpretation of Serum
Alkaline Phosphatase in Dogs
Cynthia R.L. Webster, DVM, Diplomate ACVIM, Tufts University

Profile Conditions Other Than Primary Liver

Disease Associated with Increased Serum
DEFINITION Total ALP Activity
An increase in serum ALP activity is a com-
mon, nonspecific finding in dogs that is • Bone disorders • Hypoxia/Hypotension
associated with drug induction (corticos- - Young animals (normal physiologic- - Congestive heart failure
teroids, anticonvulsants), extrahepatic dis- related finding) - Hypotensive crisis
eases (pancreatitis, endocrinopathies), or - Osteosarcoma - Severe hemolytic anemia
primary liver pathology (including nodular - Osteomyelitis - Status epilepticus
hyperplasia in older dogs). • Endocrinopathies • Neoplasia
- Diabetes mellitus - Hepatic metastasis
PROBLEMS - Hypothyroidism - Paraneoplastic induction
What is the clinical significance of an - Hyperadrenocorticism • Drug induction
increase in total ALP? Is the increase in • Gastrointestinal disease - Corticosteroids
serum total ALP associated with hepatobil- - Pancreatitis - Phenobarbital
iary disease or primary bone disorders or - Inflammatory bowel disease • Systemic infections
due to drug induction from corticosteroids
or phenobarbital? Are increases due to
corticosteroid or phenobarbital resulting Breed-specific hepatopathies in Labrador iary disease. (Specificity is the ability of the
from enzyme induction or drug-induced retrievers, Doberman pinschers, test to exclude the presence of hepatobil-
hepatotoxicity? Dalmatians, cocker spaniels, Bedlington iary disease.) The low specificity of serum
terriers, and Skye terriers should alert the total ALP is due to presence of several ALP
When increases in total ALP are due to clinician to the possibility of a primary isoenzymes (bone, liver, corticosteroid-
hepatobiliary disease, are they associated hepatobiliary disorder. induced) and the unique susceptibility of
with primary hepatobiliary disease, or do the enzyme to induction by drugs.
they represent secondary involvement of Nodular hepatic hyperplasia is a common,
the liver? Conditions in which total ALP age-related, incidental lesion in dogs with Bone ALP accounts for about one third of
may be elevated without the presence of a reported incidence from 70% to 100% in normal serum total ALP and is elevated
clinically significant hepatobiliary disease dogs older than 14 years of age. with conditions associated with increased
are listed in the Box. osteoblastic activity, such as bone growth
CAUSE/RISK FACTORS/ in young dogs, or with pathologic condi-
INCIDENCE/PREVALENCE PATHOPHYSIOLOGY tions, such as osteomyelitis, osteosarcoma,
Unknown, but increased total ALP is one The primary clinical asset of serum total or renal secondary hyperparathyroidism.3
of the most common abnormalities detect- ALP determination is its sensitivity (80%) Typically, bone ALP elevations in these
ed on biochemical profiles in dogs.1 for hepatobiliary disease.2 (Sensitivity is conditions are mild to moderate (three to
the ability of the test to detect animals five times the upper limit of normal).
SIGNALMENT that have hepatobiliary disease.) The major Liver ALP is a membrane-bound enzyme
Young dogs have increases in bone isoen- limitation in interpreting serum total ALP present on biliary epithelial cells and hepa-
zymes due to increased osteoblastic activi- is its low specificity (51%) for hepatobil- tocytes. Increases in serum liver ALP are
ty in growing bones.
ALP = alkaline phosphatase c o n t i n u e s

co n s u l t a n t o n c a l l . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . N AV C c l i n i c i a n’s b r i e f. . . . . m a rc h . 2 0 0 4 . . . . . 9
consultant on call CONTINUED

due to elution of the enzyme from the • Jaundice: Prehepatic (hemolytic ane- • Normal liver: Does not rule out primary
membrane following hepatobiliary dam- mia), hepatic, or posthepatic hyper- hepatic disease
age. The largest increases are seen with bilirubinemia • Gallbladder/biliary tree: Gallbladder
focal or diffuse intrahepatic or extrahepat- • Abdominal effusion: Chronic liver dis- mucocele, distention of intra- and/or
ic cholestasis. Mild to moderate increases ease, neoplasia, pancreatitis, congestive extrahepatic biliary tree, bile duct min-
are seen with chronic hepatitis and hepat- heart failure eralization, choleliths
ic necrosis. • Hepatomegaly: Primary liver disease, • Portal vasculature: Single or multiple
steroid hepatopathy, passive conges- acquired portosystemic shunts, portal
Corticosteroid-induced ALP is produced by tion, hepatic lipidosis vein thrombosis, passive congestion
the liver and is found on hepatocyte mem- • Dyspnea/increased lung sounds: • Pancreas: Enlarged hypoechoic, sur-
branes.4–6 This enzyme increases from de Congestive heart failure rounded by hyperechoic fat with
novo synthesis of the enzyme in dogs • Abdominal pain: Pancreatitis, cholecys- pancreatitis
exposed to endogenous or exogenous titis, gastric ulceration • Thickened gastrointestinal wall with
corticosteroid excess. • Chronic intermittent gastrointestinal retention of normal layering:
signs: Gastric ulceration secondary to Inflammatory bowel disease
chronic liver disease, congenital por- • Hepatic metastasis: Primary neoplasia
Diagnosis tosystemic shunts, chronic pancreatitis, of spleen, stomach, pancreas, intestine,
inflammatory bowel disease or adrenals
Clinical findings can be used as an aid in
identifying the source of total ALP eleva- IMAGING LABORATORY ANALYSIS
tion. Similarly, diagnostic imaging can be Radiography. • Hyperadrenocorticism: Mild poly-
helpful in determining the root of the • Hepatomegaly: Steroid hepatopathy, cythemia, mild thrombocytosis, mild to
problem, as can laboratory analysis and congestive heart failure, hepatic lipido- moderate increase in ALT and GGT,
biopsy. The following indicators are sis, and focal and diffuse hepatobiliary hypercholesterolemia
important. disease • Primary liver disease: Concurrent
• Microhepatica: Chronic end-stage increases in serum ALT, AST, and GGT;
HISTORY / PHYSICAL EXAMINATION hepatobiliary disease, congenital hypoalbuminemia; low blood urea
• History of drug administration: portosystemic shunts nitrogen; hypocholesterolemia; hypo-
Particularly corticosteroids (oral, paren- • Choleliths: 50% are visible radiographi- glycemia. Note: The specificity of the
teral, or topical) or phenobarbital, but cally and may be associated with total ALP for hepatobiliary disease can
also other potentially hepatotoxic drugs, secondary cholecystitis. be improved to 94% if used in combi-
such as potentiated sulfonamides • Decreased abdominal detail: Ascites nation with serum GGT.
and nonsteroidal antiinflammatory • Cardiomegaly and signs of pulmonary • Chronic liver disease: Pure transudate
agents edema: Congestive heart failure or modified transudate as evidenced by
• Bone pain: Osteomyelitis, osteosarcoma • Lytic bone lesion: Bone tumor or abdominal tap
• Polyuria/polydipsia: Hyperadreno- infection • Acute pancreatitis: Acute nonseptic
corticism, diabetes mellitus, chronic neutrophilic inflammation as evidenced
liver disease, congenital portosystemic Ultrasonography. by abdominal tap; increase in serum
shunts • Focal or multifocal hepatic lesions: amylase and/or lipase
• Dermatologic disorders: Hyperadreno- Hepatobiliary neoplasia, nodular hyper- • Diabetes mellitus: Persistent hyper-
corticism, hepatocutaneous syndrome plasia, metastatic disease, abscess glycemia
• Diffuse cerebral signs: Hepatic enceph- • Diffusely hyperechoic liver: Steroid • Malignancy: Malignant effusion as evi-
alopathy from chronic liver disease or hepatopathy, hepatic lipidosis, lym- denced by abdominal tap. High protein
congenital portosystemic shunts phosarcoma fluid with exfoliated neoplastic cells
• Pot belly: Abdominal wall muscle atro- • Diffusely hypoechoic liver: Passive con- (pancreatic, intestinal, adrenal adeno-
phy with centripetal redistribution of gestion, lymphosarcoma, suppurative carcinoma, or lymphoma). Absence of
fat in hyperadrenocorticism hepatitis neoplastic cells, however, does not rule

ACTH = adrenocortical hormone–stimulation test; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST aspartate transaminase; GGT = γ-glutamyl
transpeptidase; LDDS = low-dose dexamethasone suppression; PCV = packed cell volume

1 0 . . . . . m a rc h . 2 0 0 4 . . . . . N AV C c l i n i c i a n’s b r i e f . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . co n s u l t a n t o n c a l l
 out cancer. Hemorrhagic effusion with
ruptured hemangiosarcoma.

DEFINITIVE DIAGNOSIS
Disease-specific. 1
• Hyperadrenocorticism: Failure to sup-
press on an LDDS test. Exaggerated
response to an ACTH-stimulation test.
• Hepatobiliary disease: Abnormal hepatic
function test: Elevated total serum bile
acids. Hyperbilirubinemia with a normal
PCV is due to hepatic or posthepatic
disease. Blood hyperammonemia con-
firms the presence of hepatic enceph-
alopathy. Increased prothrombin time
or partial thromboplastin time can
accompany severe hepatobiliary
1
disease.
• Nodular hyperplasia: Asymptomatic Steroid hepatopathy in a dog on immune-suppressive doses of prednisone

patient, typically older than 8 years of

age with mild to moderate increase in disease, such as lipidosis, neoplasia, with ACTH stimulation; if indicated, pursue
total ALP. Other serum liver enzymes vascular, or inflammatory/fibrotic dis- testing for other adrenal steroids, such as
and hepatic function tests are normal. ease. Steroid hepatopathy is character- 17-hydroxyprogesterone. If there are no
Ultrasonography shows multifocal nod- ized by the presence of vacuoles in signs of other disease but total ALP is less
ules. Hepatic biopsy shows well-circum- hepatocytes, which most studies sug- than 2 times upper limit of normal, moni-
scribed nodules with normal but often gest are filled with glycogen5 (Figure tor total ALP monthly. If total ALP is per-
vacuolated hepatocytes surrounded by 1). May be associated with endoge- sistently elevated or more than 4 times
normal hepatic tissue. Wedge biopsy nous or exogenous administration of upper limit of normal, perform abdominal
works best, since nodular hyperplasia corticosteroids or with endogenous ultrasonography and evaluate as follows:
must be differentiated from regenera- excess of other adrenal steroids, such • Focal or diffuse liver disease: Hepatic
tive nodule in a cirrhotic liver, which as 17-hydroprogesterone.10 biopsy
requires the finding of fibrosis and/or • Bile duct obstruction in the absence of
inflammatory changes in surrounding pancreatic disease: Surgical decompres-
hepatic parenchyma. sion of biliary tract
Treatment
• Gallbladder mucocele: Cholecystectomy
Laboratory testing. • Choleliths (without obstruction) and/or
• ALP isoenzyme analysis: Determination Treatment is tailored to the specific disor-
der. Asymptomatic patients with an thickened gallbladder wall: Perform
of corticosteroid-induced increases in cholecystocentesis with bacterial cul-
ALP by levamisole inhibition is a sensi- increase in serum total ALP or patients
with primary hepatic disease on cortico- ture and bile sensitivity testing, or give
tive (95%) but not specific (18%) indi- a therapeutic trial of antibiotics and
cator of excess exposure to cortico- steroids or phenobarbital are particularly
problematic. Management of such patients choleretics (ursodeoxycholate).
steroids.7 Many dogs with primary
hepatobiliary disease have increases in is reviewed in the following discussion.
Dogs on corticosteroids.
both corticosteroid-induced ALP and Typical findings include hepatomegaly, dif-
liver ALP.8.9 Corticosteroids induce PATIENT MONITORING
Asymptomatic patients. fusely hyperechoic hepatic parenchyma on
increases in both liver and bone ALP ultrasonography, steroid hepatopathy on
along with corticosteroid-induced ALP. Look for signs of occult hyperadrenocorti-
cism. Perform an LDDS or ACTH-stimula- hepatic biopsy, moderate to marked
Phenobarbital increases liver ALP. increases in total ALP (3 to 64 times upper
• Hepatic biopsy: Identify primary hepatic tion test. Measure cortisol levels initially
c o n t i n u e s

co n s u l t a n t o n c a l l . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . N AV C c l i n i c i a n’s b r i e f. . . . . m a rc h . 2 0 0 4 . . . . . 1 1
consultant on call CONTINUED

at a glance…
limit of normal), mild to moderate increas- should be within the normal range.11,12
es in ALT and GGT (2 to 6 times upper limit Ultrasonography yields normal findings,
of normal) with little to no increase in AST and most dogs do not have hepatomegaly. Serum Total ALP
(< 2-fold increase). Biopsy shows diffuse cytoplasmic granu- • Hepatobiliary, bone, and corticos-
larity due to proliferation of smooth teroid-induced isoenzymes con-
Signs of possible hepatotoxicity include endoplasmic reticulum. tribute to total serum alkaline
abnormalities of hepatic function tests, phosphatase levels in dogs.
such as increased total serum bile acids, Signs of possible hepatotoxicity include • Elevation in the bone isoenzyme is
hyperbilirubinemia, hypoalbuminemia, abnormal hepatic function tests. ALT, GGT associated with increased
coagulopathy, ascites, or hepatic encephal- or AST elevations more than 2 times the osteoblastic activity; in osteosarco-
opathy. Hepatic biopsy shows vacuolar upper limit of normal. Hepatic biopsy ma, the degree of bone ALP eleva-
hepatopathy with areas of focal necrosis, shows chronic inflammatory/fibrotic dis- tion predicts survival time.
cholestasis, and degeneration of hepatocytes. ease.13 Treatment involves weaning from • Definitive diagnosis of induction of
phenobarbital and onto alternative anti- the corticosteroid isoenzyme is
Treatment involves discontinuing cortico- seizure medications, such as potassium made by medication history along
steroids and substituting an alternative bromide; controlling the complications of with the presence of clinical or
immunosuppressive, antiinflammatory agent, hepatic failure; and initiating hepatoprotec- laboratory signs suggestive of
such as azathioprine or chlorambucil. tive therapy with ursodeoxycholate and/or hyperadrenocorticism in combina-
S-adenosylmethionine. tion with abnormal LDDS or ACTH
Dogs on phenobarbital. stimulation.
The liver of a dog with cirrhosis due to Follow-up • Total ALP is a sensitive but rela-
chronic hepatotoxicity from phenobarbital tively nonspecific indicator of
is shown in Figure 2. Typical findings hepatobiliary disease. Specificity
include increased total ALP usually less
PROGNOSTIC SIGNIFICANCE OF ALP
for primary hepatobiliary disease
Increases in serum total ALP with primary
than 5 times upper limit of normal, with is increased when it is used in
hepatobiliary disease are indicative of
ALT usually less than 2 times upper limit of series with other liver enzymes.
active hepatobiliary disease. The increase is
normal. GGT, AST, total serum bile acids
usually—but not always—pro-
portional to the severity of
evaluation, especially in conjunction with
ongoing damage. In end-stage
hepatic biopsy or function tests. Since the
fibrotic liver disease, however,
half-life of ALP in dogs is 72 hours, a 50%
total ALP may not be elevated
decrease in total ALP over a 3- to 4-day
in proportion to the degree of
period may indicate resolution of acute
hepatic disease because of
injury. In the absence of hepatotoxicity,
enzyme depletion secondary to
serum total ALP elevations due to pheno-
replacement of normal hepato-
barbital should return to normal in 2 to 4
cytes by fibrosis.
weeks after discontinuation of the drug.
Increases in total ALP due to corticosteroid
Since the liver has large regen-
excess, however, may take several months
erative capacity and great func-
to normalize.
tional reserve, the magnitude of
elevation of total ALP is not Elevations in bone ALP are associated with
indicative of the degree of func- shorter survival time in appendicular
tional impairment and is not osteosarcoma.14 ■
prognostic. However, the prog-
nostic significance of total ALP See Aids & Resources, back page, for

2 can be improved by sequential references, contacts, and appendices.

ACTH = adrenocortical hormone–stimulation test; ALP = alkaline phosphatase; ALT = alanine

Cirrhotic liver in a dog secondary to chronic hepatotoxicity from aminotransferase; AST aspartate transaminase; GGT = γ-glutamyl transpeptidase;
phenobarbital LDDS = low-dose dexamethasone suppression

1 2 . . . . . m a rc h . 2 0 0 4 . . . . . N AV C c l i n i c i a n’s b r i e f . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . co n s u l t a n t o n c a l l