High ALP…Do I Hit The Panic
Button Or The Snooze Alarm?
Jason M. Eberhardt, DVM, MS, DACVIM
High ALP – Dazed and confused?

VERY common lab finding

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39% of ALL dogs
51% of dogs > 8 yrs old
Often a diagnostic dilemma

For liver disease

High sens. (86%) but…low spec. (49%)
Pathophysiology review

Heterogeneous group of enzymes

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Catalyze the hydrolysis of phosphate from organic
compounds in an alkaline pH
Poorly defined biologic functions
Total serum ALP

L-ALP, B-ALP, C-ALP (Dog only)

½ lives of intestinal, kidney and placenta is only minutes
Bone Alkaline Phosphatase


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Attached to the external cellular membrane of
osteoblasts
Function is unknown???
Typically young, growing dogs
 96% of total ALP in patients <1 yr

Only 25% of total ALP in patients >8 yr
Other causes of increased B-ALP
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Osteosarcoma

Typically <4x normal

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Prognostic
Fx healing, renal 2nd hyperparathyroidism,
nutritional osteopathies (rare)
Benign familial hyperphosphatasemia

Siberian huskies
Corticosteroid Alkaline Phosphatase
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Remember in dogs only!
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C-ALP 10-30% in normal dogs

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Product of the I-ALP gene expression in the liver
Expression delayed in experimental dogs
% of total ALP increases with age
Can be measured at most labs but…

What does it mean???

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Very high sensitivity for Cushing’s (95%)
Very poor specificity (18%)
Liver Alkaline Phosphatase

Located predominantly in the periportal zone

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Bile canaliculi and sinusoidal membranes
L-ALP is predominate isoenzyme in dogs >1 yr
Two mechanisms for increase

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Cholestasis
Drug induction

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Phenobarbital
Exogenous steroids
Differentials for increased ALP
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B-ALP
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C-ALP
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Intrahepatic cholestasis

Nodular hyperplasia, Neoplasia, Chronic hepatitis/cirrhosis, Vacuolar
hepatopathy, Infectious/inflammatory, Toxic, hepatocutaneous syndrome
Extrahepatic cholestasis

Pancreatitis, Biliary disease, Mucocele, Cholangitis/cholangiohepatits,
Neoplasia (biliary, duodenum, pancreas), Cholelithiasis
Secondary/reactive

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Cushing’s, exogenous corticosteroids
Cholestasis

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Young animals, bone neoplasia, nutritional osteopathy, hyperparathyroisim
Chronic disease-Neoplasia, infection/inflammation, pancreatitis
Gastrointestinal disease
Endocrine (hypothyroid, DM, hypertriglyceridemia in Min. Sch.)
Induction (drugs)
Breed-related
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Siberian huskies, Scottish terriers
Common conditions causing only
increased ALP
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Cushing’s disease
Drug induction
Idiopathic vacuolar hepatopathy
Hepatic neoplasia
Nodular hyperplasia
Breed-related
How high is too high???
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Degree of increase does not correspond with
degree of illness

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Dogs with ALP associated disease
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Makes it more likely?
1,950 +/- 1,300 U/L
Dogs without disease

970 +/- 430 U/L
(Nestor et al.)
Does high ALP cause signs?
NO!!!
 No patient has ever died from a
high ALP
 There is little/no evidence that high
ALP makes you ill


The enzyme does not do the harm the
underlying disease does
The diagnostic dilemma begins
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Review the record!!!
Signalment
 Clinical history
 Drug history
 Physical examination findings
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Questions to ask yourself…
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What is the patient’s age and breed?
What medications is the patient on?
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Topicals and inhaled
WHY was the blood work performed?
Is the elevation repeatable?
More questions to ask…
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Any clinical signs of Cushing’s dz?
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Other biochemical changes?
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Before the blood work was performed?
Hepatic, biliary or pancreatic disease?
Does the patient have any evidence of
systemic illness?
Beyond a CBC, Chemistry and UA
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Abdominal ultrasound
Endocrine testing
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Urine cortisol:creatinine ratio
LDDS
ACTH stimulation test
Tennessee adrenal panel
Bile acids
Liver aspirate/biopsy
Valley Fever titer???
Thoracic radiographs???
How to avoid running every test…


There is no “best” order to perform
diagnostic tests for all patients
Diagnostic plans should be
individualized

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Minimize invasiveness
Maximize owners financial resources
“Rainy” Bates 9 yr FS Aussie mix
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Presented for PU/PD, very happy otherwise
PE – Dorsal alopecia, slightly pendulous abd.
Initial ALP was 2200 U/L, ALT 300
USG 1.012 with 2+ protein
“Rainy” Bates 9 yr FS Aussie mix
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What is the patient’s age and breed?


What medications is the patient on?
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None
Why was the blood work performed?
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Middle aged FS Aussie X
PU/PD
Is the elevation repeatable?
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No
“Rainy” Bates 9 yr FS Aussie mix
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Any clinical signs of Cushing’s dz?
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Other biochemical changes?
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YES!
No
Does the patient have any evidence of
systemic illness?

No
“Rainy” Bates 9 yr FS Aussie mix
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Abdominal ultrasound
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ACTH stimulation
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Bilateral enlarged adrenal glands
Homegenously enlarged liver
Consistent with Cushing’s Dz – go figure
Lysodren therapy
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ALP 245 U/L
“Fionna” 8 yr FS Scottish Terrier
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Presented for dental
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Initial ALP 650 U/L, ALT WNL, USG 1.024
Dental was performed with no complications
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Normal clinically
Post-procedural antibiotics for 10 days
ALP eight weeks later was 960 U/L
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16 weeks later patient ALP was 830 U/L
Owners now say Fionna may increased thirst
“Fionna” 8 yr FS Scottish Terrier
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What is the patient’s age and breed
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What medications is the patient receiving
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None (1 round of antibiotics)
Why was the blood work performed?

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Middle age Scottish terrier
Pre-op Dental
Is the elevation repeatable?

Yes
“Fionna” 8 yr FS Scottish Terrier
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Are there any clinical signs of Cushing’s
disease?

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Are there other biochemical changes
suggestive of hepatic, biliary or pancreatic
disease?
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???
No
Does the patient have any evidence of
systemic illness?

No
Next step?
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UA
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Abdominal ultrasound
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WNL
ACTH stimulation
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USG 1.020
No proteinuria
Pre – 7
Bile acids
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WNL
Post - 18
Liver Biopsy
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Vacuolar hepatopathy
More???
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Tennessee Adrenal panel
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17-hydroxyprogesterone was increased
Thank goodness!
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Refer to trusty Tennessee Adrenal panel treatment
options worksheet
Apparently healthy Scottish Terriers
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Nestor et al.
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Had significantly higher mean serum ALP activity
then control dogs
2.4 times more likely to have a disease associated
with high ALP
Zimmerman et al.
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More likely to have exaggerated adrenal panel
and histological changes
12/17 w/high ALP
10/17 dogs in control group
“Rusty” Hughes 4 yr MN Labrador
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Previously dx with CNS Valley Fever
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Phenobarbital, prednisone, fluconazole x 4 mo.
2 weeks after starting meds ALP 1050 U/L
11,500 U/L – 1 mo. (put on SAM-e)
29,000 U/L – 4 mo.
32,000 U/L – 5 mo. (0.5 mg/kg/d)
Evidence of iatrogenic Cushing’s disease
“Rusty” Hughes 4 yr MN Labrador
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What is the patient’s age and breed
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What medications is the patient receiving
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Prednisone, Pb, Fluconazole
Why was the blood work performed?
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Young Labrador
CNS Valley Fever
Evidence of iatrogenic Cushing’s
Is the elevation repeatable?
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Yes
“Rusty” Hughes 4 yr MN Labrador
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Are there any clinical signs of Cushing’s
disease?

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Are there other biochemical changes
suggestive of hepatic, biliary or pancreatic
disease?

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Yes
???
Does the patient have any evidence of
systemic illness?

Yes
“Rusty” Hughes 4 yr MN Labrador
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Abdominal ultrasound
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Enlarged and uniformly hyperechoic liver
Gallbladder WNL
Further plan?
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Taper off of steroids and phenobarbital!
“Rusty” Hughes 4 yr MN Labrador
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1 mo. off of steroids
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Owner gave 2-3 dosage of steroids
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1,335 U/L
ALP 2,200 U/L
Currently only on Fluconazole and
Zonisamide
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ALP 750 U/L
“Zoe” Marsh 9 yr FS Lhasa Apso
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History of IMHA
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ALP 190 U/L – Prior to tx
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Abdominal U/S – WNL
ALP 540 U/L – During therapy (2 mg/kg)
In complete remission and off of therapy for 9 mo.
Presented for recheck
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Clinically normal
ALP 840 U/L
Rest of CBC/Chem/UA WNL
“Zoe” Marsh 9 yr FS Lhasa Apso
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UCC - WNL
Repeat abdominal U/S
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Placed on antibiotics and ursodiol
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“Sludge” in the Gallbladder
Maintained on ursodiol
Started SAM-e
5 months later…
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ALP 2780 U/L
Cholesterol is 420 mg/dL
Mild non-regenerative anemia (HCT 35%)
“Zoe” Marsh 9 yr FS Lhasa Apso
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What’s the patient’s age and breed
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What medications is the patient receiving
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Hx of steroids - none recently
Ursodiol for previous 5 mo.
SAM-e for previous 2 mo.
Why was the blood work performed?

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Middle aged Lhasa
Monitoring of ALP
Is the elevation repeatable?
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Yes…and increasing
“Zoe” Marsh 9 yr FS Lhasa Apso
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Are there any clinical signs of Cushing’s
disease?


Are there other biochemical changes
suggestive of hepatic, biliary or pancreatic
disease?


No
Gallbladder “sludge”
Does the patient have any evidence of
systemic illness?

Yes – Mild non-regenerative anemia
Plan???
 ACTH
stim?
 Bile Acids?
 Liver Bx?
What I did…
Total T4 – WNL
 Repeat abdominal ultrasound
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Surgery???
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Cholecystectomy + Bile culture + Liver biopsy
Bile culture

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GB histopathology
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Negative
Biliary mucocele
Liver histopathology

Mild-moderate vacuolar hepatopathy
Follow-up
Continued ursodiol
 ALP 2 months after surgery
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345 U/L
“Roxy” Milho 10 yr FS Rottie mix
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Poor appetite and weight loss for last 23 months
ALP is 278 U/L
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Rest of Blood work/UA is non-remarkable
Several drug trials including recent
prednisone
“Roxy” Milho 10 yr FS Rottie mix

What’s the patient’s age and breed


What medications is the patient receiving

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Has been on steroids recently
Why was the blood work performed?


Old Rottie mix
Decreased appetite and weight loss
Is the elevation repeatable?

???
“Roxy” Milho 10 yr FS Rottie mix

Are there any clinical signs of Cushing’s
disease?


Are there other biochemical changes
suggestive of hepatic, biliary or pancreatic
disease?


No
No
Does the patient have any evidence of
systemic illness?

Yes
In conclusion…


Focus on the patients’ clinical signs as much
(if not more) then the degree of increase
Finding a cause requires a systematic
approach




Remember your pathophysiology
Thoroughly review the record
Ask yourself the “ALP” questions
Develop a tailored patient plan
QUESTIONS???