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High ALP…Do I Hit The Panic Button Or The Snooze Alarm?

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%).

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High ALP…Do I Hit The Panic Button Or The Snooze Alarm?

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  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 1.012 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? • No

  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? • No

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

  25. Liver Biopsy • Vacuolar hepatopathy

  26. More??? • Tennessee Adrenal panel • 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? • Yes

  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

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

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

  41. “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

  42. “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? • ???

  43. “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? • No • Does the patient have any evidence of systemic illness? • Yes

  44. 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

  45. QUESTIONS???

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