1. High ALP…Do I Hit The Panic Button Or The Snooze Alarm?
Jason M. Eberhardt, DVM, MS, DACVIM    

2. High ALP – Dazed and confused?
VERY common lab finding
39% of ALL dogs
51% of dogs > 8 yrs old
Often a diagnostic dilemma
For liver disease
High sens. (86%) but…low spec. (49%)

3. Pathophysiology review
Heterogeneous group of enzymes
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

4. Bone Alkaline Phosphatase
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

5. Other causes of increased B-ALP
Osteosarcoma
Typically <4x normal
Prognostic
Fx healing, renal 2nd hyperparathyroidism, nutritional osteopathies (rare)
Benign familial hyperphosphatasemia
Siberian huskies

6. Corticosteroid Alkaline Phosphatase
Remember in dogs only!
Product of the I-ALP gene expression in the liver
Expression delayed in experimental dogs
C-ALP 10-30% in normal dogs
% of total ALP increases with age
Can be measured at most labs but…
What does it mean???
Very high sensitivity for Cushing’s (95%)
Very poor specificity (18%)

7. Liver Alkaline Phosphatase
Located predominantly in the periportal zone
Bile canaliculi and sinusoidal membranes
L-ALP is predominate isoenzyme in dogs >1 yr
Two mechanisms for increase
Cholestasis
Drug induction
Phenobarbital
Exogenous steroids

8. Differentials for increased ALP
B-ALP
Young animals, bone neoplasia, nutritional osteopathy, hyperparathyroisim
C-ALP
Cushing’s, exogenous corticosteroids
Cholestasis
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
Chronic disease-Neoplasia, infection/inflammation, pancreatitis
Gastrointestinal disease
Endocrine (hypothyroid, DM, hypertriglyceridemia in Min. Sch.)
Induction (drugs)
Breed-related
Siberian huskies, Scottish terriers

9. Common conditions causing only increased ALP
Cushing’s disease
Drug induction
Idiopathic vacuolar hepatopathy
Hepatic neoplasia
Nodular hyperplasia
Breed-related

10. How high is too high???
Degree of increase does not correspond with degree of illness
Makes it more likely?
Dogs with ALP associated disease
1,950 +/- 1,300 U/L
Dogs without disease
970 +/- 430 U/L
(Nestor et al.)

11. 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

12. The diagnostic dilemma begins
Review the record!!!
Signalment
Clinical history
Drug history
Physical examination findings

13. Questions to ask yourself…
What is the patient’s age and breed?
What medications is the patient on?
Topicals and inhaled
WHY was the blood work performed?
Is the elevation repeatable?

14. More questions to ask… Any clinical signs of Cushing’s dz?
Before the blood work was performed?
Other biochemical changes?
Hepatic, biliary or pancreatic disease?
Does the patient have any evidence of systemic illness?

15. Beyond a CBC, Chemistry and UA
Abdominal ultrasound
Endocrine testing
Urine cortisol:creatinine ratio
LDDS
ACTH stimulation test
Tennessee adrenal panel
Bile acids
Liver aspirate/biopsy
Valley Fever titer???
Thoracic radiographs???

16. How to avoid running every test…
There is no “best” order to perform diagnostic tests for all patients
Diagnostic plans should be individualized
Minimize invasiveness
Maximize owners financial resources

17. “Rainy” Bates 9 yr FS Aussie mix
Presented for PU/PD, very happy otherwise
PE – Dorsal alopecia, slightly pendulous abd.
Initial ALP was 2200 U/L, ALT 300
USG with 2+ protein

18. “Rainy” Bates 9 yr FS Aussie mix
What is the patient’s age and breed?
Middle aged FS Aussie X
What medications is the patient on?
None
Why was the blood work performed?
PU/PD
Is the elevation repeatable? No

19. “Rainy” Bates 9 yr FS Aussie mix
Any clinical signs of Cushing’s dz?
YES!
Other biochemical changes? No
Does the patient have any evidence of systemic illness?

20. “Rainy” Bates 9 yr FS Aussie mix
Abdominal ultrasound
Bilateral enlarged adrenal glands
Homegenously enlarged liver
ACTH stimulation
Consistent with Cushing’s Dz – go figure
Lysodren therapy
ALP 245 U/L

21. “Fionna” 8 yr FS Scottish Terrier
Presented for dental
Normal clinically
Initial ALP 650 U/L, ALT WNL, USG 1.024
Dental was performed with no complications
Post-procedural antibiotics for 10 days
ALP eight weeks later was 960 U/L
16 weeks later patient ALP was 830 U/L
Owners now say Fionna may increased thirst

22. “Fionna” 8 yr FS Scottish Terrier
What is the patient’s age and breed
Middle age Scottish terrier
What medications is the patient receiving
None (1 round of antibiotics)
Why was the blood work performed?
Pre-op Dental
Is the elevation repeatable?
Yes

23. “Fionna” 8 yr FS Scottish Terrier
Are there any clinical signs of Cushing’s disease?
???
Are there other biochemical changes suggestive of hepatic, biliary or pancreatic disease? No
Does the patient have any evidence of systemic illness?

24. Next step? UA Abdominal ultrasound ACTH stimulation Bile acids
USG 1.020
No proteinuria
Abdominal ultrasound
WNL
ACTH stimulation
Pre – 7 Post - 18
Bile acids

25. Liver Biopsy
Vacuolar hepatopathy

26. More??? Tennessee Adrenal panel Thank goodness!
17-hydroxyprogesterone was increased
Thank goodness!
Refer to trusty Tennessee Adrenal panel treatment options worksheet

27. Apparently healthy Scottish Terriers
Nestor et al.
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.
More likely to have exaggerated adrenal panel and histological changes
12/17 w/high ALP
10/17 dogs in control group

28. “Rusty” Hughes 4 yr MN Labrador
Previously dx with CNS Valley Fever
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

29. “Rusty” Hughes 4 yr MN Labrador
What is the patient’s age and breed
Young Labrador
What medications is the patient receiving
Prednisone, Pb, Fluconazole
Why was the blood work performed?
CNS Valley Fever
Evidence of iatrogenic Cushing’s
Is the elevation repeatable?
Yes

30. “Rusty” Hughes 4 yr MN Labrador
Are there any clinical signs of Cushing’s disease?
Yes
Are there other biochemical changes suggestive of hepatic, biliary or pancreatic disease?
???
Does the patient have any evidence of systemic illness?

31. “Rusty” Hughes 4 yr MN Labrador
Abdominal ultrasound
Enlarged and uniformly hyperechoic liver
Gallbladder WNL
Further plan?
Taper off of steroids and phenobarbital!

32. “Rusty” Hughes 4 yr MN Labrador
1 mo. off of steroids
1,335 U/L
Owner gave 2-3 dosage of steroids
ALP 2,200 U/L
Currently only on Fluconazole and Zonisamide
ALP 750 U/L

33. “Zoe” Marsh 9 yr FS Lhasa Apso
History of IMHA
ALP 190 U/L – Prior to tx
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
Clinically normal
ALP 840 U/L
Rest of CBC/Chem/UA WNL

34. “Zoe” Marsh 9 yr FS Lhasa Apso
UCC - WNL
Repeat abdominal U/S
“Sludge” in the Gallbladder
Placed on antibiotics and ursodiol
Maintained on ursodiol
Started SAM-e
5 months later…
ALP 2780 U/L
Cholesterol is 420 mg/dL
Mild non-regenerative anemia (HCT 35%)

35. “Zoe” Marsh 9 yr FS Lhasa Apso
What’s the patient’s age and breed
Middle aged Lhasa
What medications is the patient receiving
Hx of steroids - none recently
Ursodiol for previous 5 mo.
SAM-e for previous 2 mo.
Why was the blood work performed?
Monitoring of ALP
Is the elevation repeatable?
Yes…and increasing

36. “Zoe” Marsh 9 yr FS Lhasa Apso
Are there any clinical signs of Cushing’s disease? No
Are there other biochemical changes suggestive of hepatic, biliary or pancreatic disease?
Gallbladder “sludge”
Does the patient have any evidence of systemic illness?
Yes – Mild non-regenerative anemia

37. Plan???
ACTH stim?
Bile Acids?
Liver Bx?

38. What I did…
Total T4 – WNL
Repeat abdominal ultrasound

41. Surgery??? Cholecystectomy + Bile culture + Liver biopsy Bile culture
Negative
GB histopathology
Biliary mucocele
Liver histopathology
Mild-moderate vacuolar hepatopathy

42. Follow-up
Continued ursodiol
ALP 2 months after surgery
345 U/L

43. “Roxy” Milho 10 yr FS Rottie mix
Poor appetite and weight loss for last 2-3 months
ALP is 278 U/L
Rest of Blood work/UA is non-remarkable
Several drug trials including recent prednisone

44. “Roxy” Milho 10 yr FS Rottie mix
What’s the patient’s age and breed
Old Rottie mix
What medications is the patient receiving
Has been on steroids recently
Why was the blood work performed?
Decreased appetite and weight loss
Is the elevation repeatable?
???

45. “Roxy” Milho 10 yr FS Rottie mix
Are there any clinical signs of Cushing’s disease? No
Are there other biochemical changes suggestive of hepatic, biliary or pancreatic disease?
Does the patient have any evidence of systemic illness?
Yes

47. 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

48. QUESTIONS???