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 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 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 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 Osteosarcoma Typically <4x normal Prognostic Fx healing, renal 2nd hyperparathyroidism, nutritional osteopathies (rare) Benign familial hyperphosphatasemia Siberian huskies

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%)

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

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

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

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.)

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 Review the record!!! Signalment Clinical history Drug history Physical examination findings

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?

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?

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???

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

“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 1.012 with 2+ protein

“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

“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?

“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

“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

“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

“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?

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

Liver Biopsy Vacuolar hepatopathy

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

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

“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

“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

“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?

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

“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

“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

“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%)

“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

“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

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

What I did… Total T4 – WNL Repeat abdominal ultrasound

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

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

“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

“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? ???

“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

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???