Interpretation of Serum Alkaline Phosphatase in Dogs

Overview

Increased serum alkaline phosphatase (ALP) activity is a common finding in dogs and can be a result of primary hepatobiliary or bone disease, secondary to reactive hepatopathies, or caused by drug induction.^1,2 Clinical presentation, clinical pathologic findings, and diagnostic imaging can be used as noninvasive aides in identification of the source of total ALP elevation.

Epidemiology

Incidence/Prevalence

In a study that included 1,022 blood samples from healthy and sick dogs, serum ALP activity increased in 39% of dogs (71% in dogs <1 year of age, 28% in dogs 1-8 years of age, 51% in dogs >8 years of age).³ The high incidence in dogs <1 year of age reflects increases in the bone isoenzyme because of osteoblastic activity in growing bone. The increase in dogs >8 years of age is likely associated with high incidence of benign nodular hyperplasia in older dogs.⁴

Signalment

Breed Predisposition⁵

• Breed-specific hepatobiliary disorders suggest the possibility of a primary hepatobiliary disorder and should guide clinical decision-making.

• Examples include

  • Gallbladder mucoceles

    • Shetland sheepdogs

    • Border terriers

  • Chronic hepatitis

    • Labrador retrievers

    • Doberman pinschers

    • Dalmatians

    • American and English cocker spaniels

    • English springer spaniels

    • West Highland white terriers

    • Bedlington terriers

  • Vacuolar hepatopathies

    • Scottish terriers

    • Miniature schnauzers

Age

• Young dogs have increases in bone isoenzymes because of increased osteoblastic activity in growing bones.

• Benign nodular hyperplasia is a common, age-related, incidental lesion in dogs; reported incidence ranges from 70% to 100% in dogs >10 years of age.⁴

Physiology

The primary clinical asset of serum total ALP determination is the ability (80%) to detect patients with hepatobiliary disease (ie, sensitivity).^1,2,5,6 The major limitation in interpreting serum total ALP is low ability (51%) to exclude the presence of hepatobiliary disease (ie, specificity). The low specificity of serum total ALP is due to the presence of several ALP isoenzymes (ie, bone, liver, corticosteroid-induced) and the unique susceptibility of the enzyme to induction by drugs.^1,2,5,6

Bone Isoenzymes

The bone isoenzyme of ALP accounts for approximately one-third of normal serum total ALP activity and is elevated in conditions associated with increased osteoblastic activity (eg, bone growth in young dogs) or in dogs with pathologic conditions (eg, osteomyelitis, osteosarcoma, renal secondary hyperparathyroidism).⁴ Serum bone ALP elevations in patients with these conditions are typically mild to moderate (3-5 times the upper limit of normal).^1,7

Liver Isoenzymes

The liver isoenzyme of ALP is a membrane-bound enzyme present on biliary epithelial cells and hepatocytes. Increases in serum liver ALP activity are caused by elution of the enzyme from the membrane following hepatobiliary damage. The largest increases occur with focal or diffuse intrahepatic or extrahepatic cholestasis. Mild to moderate increases occur with chronic hepatitis and hepatic necrosis.

Corticosteroid-Induced Isoenzymes

The corticosteroid-induced isoenzyme of ALP is produced by the liver and found on hepatocyte membranes.^1,2 This enzyme increases from de novo synthesis of the enzyme in dogs exposed to endogenous or exogenous corticosteroid excess.

Potential Causes of Changes in Serum ALP Activity

Determining the clinical significance of an increase in total serum ALP activity can be challenging. In dogs, ALP isoenzymes originate from the bone or the liver or can be induced by drugs in the absence of hepatobiliary damage (see Drugs Commonly Associated With Increased Serum ALP Activity). In addition, benign nodular hyperplasia, a clinically silent morphologic change in the liver, is a common cause of increased serum ALP in older dogs. An increase can also be caused by reactive hepatopathies that occur due to nonhepatobiliary disease in the splanchnic bed.^1,2

Conditions in which total serum ALP activity may be elevated without the presence of clinically significant hepatobiliary disease are listed in Conditions Other Than Primary Liver Disease Associated With Increased Serum Total ALP Activity.

Drugs Commonly Associated With Increased Serum ALP Activity

• Typical findings in dogs receiving corticosteroids include hepatomegaly, diffuse hyperechoic hepatic parenchyma on ultrasonography, vacuolar hepatopathy on hepatic biopsy, moderate to marked increases in total serum ALP and gamma-glutamyl transferase (GGT) activity with significant individual variability in the extent of induction (3-50 times the upper limit of normal) and little to no increase in serum transaminases (increase <2 times that of normal).^12,13

• Rarely, corticosteroids can be associated with hepatotoxicity.

  • Signs of possible hepatotoxicity include abnormalities of hepatic function tests (eg, increased total serum bile acids, hyperbilirubinemia, hypoalbuminemia, moderate to marked increases in serum transaminases).

  • Hepatic biopsy shows severe vacuolar hepatopathy with areas of focal necrosis, cholestasis, and ballooning degeneration of hepatocytes.^12,13

  • Therapy involves treatment of hyperadrenocorticism or discontinuation of corticosteroids and substitution of an alternative immunosuppressive or anti-inflammatory agent.

• Typical findings associated with enzyme induction caused by phenobarbital include increased total serum ALP activity, usually <5 times the upper limit of normal with normal to minimal increases in serum ALT, AST, and GGT activity.

  • Ultrasonography is typically normal, and most dogs do not have hepatomegaly.

  • Biopsy shows diffuse cytoplasmic granularity caused by proliferation of smooth endoplasmic reticulum.^10,11

• Phenobarbital is a known hepatotoxin. The liver of a dog with cirrhosis as a result of chronic hepatotoxicity from phenobarbital is shown in Figure 1.

  • Signs of hepatotoxicity include abnormal hepatic function tests (total serum bile acids, hypoalbuminemia, hyperbilirubinemia).

  • Elevations in serum ALT, AST, or GGT activity occur.

  • Hepatic biopsy shows chronic inflammatory/fibrotic disease.¹³

  • Treatment involves rapid tapering off from phenobarbital and changing to an alternative antiseizure medication, controlling the complications of hepatic failure, and initiating hepatoprotective therapy with ursodiol and/or S-adenosylmethionine.^10,11

FIGURE 1 Drug-induced hepatopathy seen in the liver of a dog receiving phenobarbital antiseizure therapy

• Multiple studies of dogs receiving cannabidiol preparations have shown that increases in serum ALP activity are possible, with a smaller number having serum ALT elevations.^8,9

  • Evaluation to determine whether these increases in liver enzymes cause morphologic lesions has been limited.

  • Enzyme elevations are more common in dogs also receiving dual therapy with antiepileptic drugs or NSAIDs.^8,9

Next Steps When Evaluating Patients With Abnormal Values

Patient History

• History of drug administration

  • Particularly corticosteroids (oral, parenteral, or topical) or phenobarbital, but also other potentially hepatotoxic drugs (eg, cannabidiols, potentiated sulfonamides, NSAIDs)^8-13

  • Both phenobarbital and corticosteroids can induce production of ALP but are also capable of causing hepatotoxicity. In cases of hepatotoxicity, serum transaminases not induced by these drugs are typically elevated.

• Polyuria/polydipsia

  • Potential causes include hyperadrenocorticism, diabetes mellitus, chronic liver disease, and congenital portosystemic shunts.

• History of dermatologic disorders

  • Potential causes include hyperadrenocorticism and hepatocutaneous syndrome.

• Chronic intermittent GI signs

  • Potential causes include gastric ulceration secondary to chronic liver disease, congenital portosystemic shunts, chronic pancreatitis, and inflammatory bowel disease.

Physical Examination Findings & Potential Causes

• Bone pain

  • Osteomyelitis, osteosarcoma

• Diffuse cerebral signs

  • Hepatic encephalopathy from chronic liver disease or congenital portosystemic shunts

• Potbelly

  • Abdominal wall muscle atrophy with centripetal redistribution of fat in hyperadrenocorticism

• Jaundice

  • Prehepatic (eg, hemolytic anemia), hepatic, or posthepatic hyperbilirubinemia

• Abdominal effusion

  • Chronic liver disease, neoplasia, pancreatitis, congestive heart failure

• Hepatomegaly

  • Primary liver disease, vacuolar hepatopathy, passive congestion, hepatic lipidosis

• Dyspnea/increased lung sounds

  • Congestive heart failure

• Abdominal pain

  • Pancreatitis, cholecystitis, gastric ulceration

Relevant Diagnostic Testing, Findings, & Potential Causes^14-22

Diagnostic Imaging

Radiography

• Hepatomegaly

  • Vacuolar hepatopathy, congestive heart failure, hepatic lipidosis, focal and diffuse hepatobiliary disease

• Microhepatica

  • Chronic end-stage hepatobiliary disease (eg, cirrhosis), congenital portosystemic shunts.

• Choleliths

  • 50% visible on radiographs, may be associated with secondary cholecystitis

• Decreased abdominal detail

  • Ascites

• Cardiomegaly and signs of pulmonary edema

  • Congestive heart failure

• Lytic bone lesion

  • Bone tumor or infection

• Normal liver

  • Does not rule out primary hepatic disease

Ultrasonography

• Focal lesion

  • Hepatocellular carcinoma, hepatocellular adenoma, other cancers, abscess

• Multifocal hepatic lesions

  • Benign nodular hyperplasia, vacuolar hepatopathy, metastatic disease, chronic hepatitis (eg, chronic granulomatous hepatitis)^14,15

• Diffuse hyperechoic liver

  • Vacuolar hepatopathy, hepatic lipidosis, lymphosarcoma

• Diffuse hypoechoic liver

  • Passive congestion, lymphosarcoma, infectious hepatitis

• Gallbladder/biliary tree

  • Gallbladder mucocele (diagnostic), distention of intra- and/or extrahepatic biliary tree, bile duct mineralization, choleliths^17-19

• Portal vasculature

  • Single or multiple acquired portosystemic shunts, portal vein thrombosis

• Pancreas

  • Enlarged, hypoechoic, and surrounded by hyperechoic fat with pancreatitis

• Thickened GI wall with retention of normal layering

  • Inflammatory bowel disease

• Hepatic metastasis

  • Primary neoplasia of the spleen, stomach, pancreas, intestine, or adrenals

• Honeycomb Liver

  • Hepatocutaneous syndrome²⁰

• Normal liver

  • Does not rule out primary hepatic disease

Laboratory Analysis

• CBC

• Serum chemistry profile

• Urinalysis

• Cytology of abdominal effusion

• Hepatic biopsy

  • Identifies primary hepatic disease (eg, vacuolar disease [lipid or glycogen accumulation], neoplasia, vascular hypoperfusion, inflammatory/fibrotic disease)

  • Permits determination of hepatic copper levels to aid in diagnosis of copper-associated hepatopathy²³

• ALP isoenzyme analysis

  • Limited value

  • Determination of corticosteroid-induced increases in serum ALP via levamisole inhibition is a sensitive (95%) but not specific (18%) indicator of excess exposure to corticosteroids.

  • Many dogs with primary hepatobiliary disease have increases in both corticosteroid-induced isoenzymes and liver isoenzymes.

  • Corticosteroids induce increases in liver and bone isoenzymes, along with corticosteroid-induced isoenzymes.

  • Phenobarbital increases liver isoenzymes.^24,25

• Disease-specific testing

  • Hyperadrenocorticism

    • Low-dose dexamethasone suppression (LDDS) test

    • ACTH stimulation test

  • Hepatobiliary disease

    • Hepatic function test

    • Total serum bile acids

    • Blood ammonia levels

    • Prothrombin or partial thromboplastin time

  • Nodular hyperplasia

    • Hepatic function test

    • Hepatic biopsy

Disease-Specific Findings

• Hyperadrenocorticism

  • Mild polycythemia, mild thrombocytosis, mild to moderate increase in serum ALP and GGT activity, hyperlipidemia, isosthenuria with mild proteinuria

  • Failure to suppress on an LDDS test, exaggerated response to an ACTH-stimulation test

• Primary hepatobiliary disease

  • Concurrent increases in serum ALT, AST, and/or GGT; hyperbilirubinemia, hypoalbuminemia; low BUN; hypocholesterolemia; hypoglycemia

  • Abnormal hepatic function test

  • Elevated total serum bile acids

  • Hyperbilirubinemia with a normal packed-cell volume due to hepatic or posthepatic disease

  • Blood hyperammonemia

    • Confirms the presence of hepatic encephalopathy

  • Increased prothrombin time or partial thromboplastin time can accompany acute or chronic liver failure.^14,15

  • Abdominal effusion consistent with a pure transudate or modified transudate on cytologic evaluation with chronic liver disease

• Nodular hyperplasia

  • Subclinical patient, typically >8 years of age

  • Mild to moderate increase in total serum ALP activity that does not increase quickly over time

  • Other serum liver enzymes and hepatic function tests are normal.

  • Ultrasonography shows multifocal nodules.

  • Hepatic biopsy shows well-circumscribed nodules with normal but often vacuolated hepatocytes surrounded by normal hepatic tissue.

    • Wedge biopsy is optimal because nodular hyperplasia must be differentiated from a regenerative nodule in a cirrhotic liver, which requires fibrosis and/or inflammatory changes in the surrounding hepatic parenchyma.⁴

• Acute pancreatitis

  • Abdominal effusion consistent with acute, nonseptic neutrophilic inflammation

  • Increase in serum amylase and/or lipase or immunoreactive pancreatic lipase

• Diabetes mellitus

  • Persistent hyperglycemia

• Malignancy

  • Malignant effusion, high protein fluid with exfoliated neoplastic cells (pancreatic, intestinal, adrenal adenocarcinoma, or lymphoma), absence of neoplastic cells (does not rule out cancer), hemorrhagic effusion with ruptured hemangiosarcoma

Treatment

• Treatment should be based on the specific cause of the increase in serum ALP activity.

Monitoring & Follow-Up

Subclinical Patients

• Observation for signs of occult hyperadrenocorticism; LDDS or ACTH-stimulation test should be performed.

• If there are no signs of another disease process and total ALP is <5 times the upper limit of normal, total serum ALP activity should be monitored periodically.

  • The typical pattern of benign nodular hyperplasia is a very slow progression in serum ALP activity over many years without increases in other serum liver enzyme activity.

• If total ALP is persistently elevated, abdominal ultrasonography should be performed and evaluated.

  • Multiple nodules with normal to increased liver size are most consistent with benign nodular hyperplasia but can also be due to metastatic disease or round cell neoplasia. Failure to identify a primary tumor on abdominal ultrasonography helps differentiate benign nodular hyperplasia from metastatic disease. Dogs with round cell disease are not typically subclinical.

  • Multiple nodules in a small liver with irregular margins is consistent with a diagnosis of cirrhosis. Laparoscopic hepatic biopsy is needed to confirm the diagnosis.

• Focal mass

  • Percutaneous biopsy or fine-needle aspiration

• Gallbladder mucocele

  • Evaluation for medical versus surgical (cholecystectomy) management^17,18

• Choleliths (without obstruction) with evidence of gallbladder wall pathology

  • Cholecystocentesis with bacterial culture and sensitivity of bile or therapeutic trial of antibiotics and choleretics (ursodiol)

Patients With Clinical Signs

• Diagnostics for detection of a primary or secondary hepatobiliary disorder (eg, hepatic tumor or abscess, gallbladder mucocele, cholecystitis, chronic hepatitis, cirrhosis, pancreatitis, extrahepatic bile duct obstruction), typically including CBC, serum chemistry profile, urinalysis, and abdominal ultrasonography, should be performed.

• Additional hepatic function tests (eg, total serum bile acids, blood ammonia) may be necessary.

• Advanced imaging or hepatic biopsy may be necessary for definitive diagnosis.^23,26

Prognostic Significance

Increases in serum ALP activity in dogs with primary hepatobiliary disease are indicative of active hepatobiliary disease. Increase is usually, but not always, proportional to the severity of ongoing damage. In patients with end-stage fibrotic liver disease, serum ALP activity may not be elevated in proportion to the degree of hepatic disease because of enzyme depletion secondary to replacement of normal hepatocytes by fibrosis.

The liver has a large regenerative capacity and great functional reserve, thus the magnitude of elevation of serum ALP is not indicative of the degree of functional impairment and is not prognostic; however, the prognostic significance of total serum ALP can be improved by sequential evaluation, especially in conjunction with hepatic biopsy or function tests. The half-life of serum ALP in dogs is 72 hours; a 50% decrease in total ALP over a 3- to 4-day period may therefore indicate resolution of acute injury. In the absence of hepatotoxicity, serum ALP elevations caused by phenobarbital should return to normal 2 to 4 weeks after discontinuation of the drug. Increases in total ALP due to corticosteroid excess, however, may take several months to normalize.

Elevations in bone ALP are associated with shorter survival times in patients with appendicular osteosarcoma.⁷