High ALP

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High ALPDo I Hit The Panic Button Or The Snooze
Alarm?

• Jason M. Eberhardt, DVM, MS, DACVIM    

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High ALP Dazed and confused?

• VERY common lab finding
• 39 of ALL dogs
• 51 of dogs gt 8 yrs old
• Often a diagnostic dilemma
• For liver disease
• High sens. (86) butlow spec. (49)

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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

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Bone Alkaline Phosphatase

• Attached to the external cellular membrane of
  osteoblasts
• Function is unknown???
• Typically young, growing dogs
• 96 of total ALP in patients lt1 yr
• Only 25 of total ALP in patients gt8 yr

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Other causes of increased B-ALP

• Osteosarcoma
• Typically lt4x normal
• Prognostic
• Fx healing, renal 2nd hyperparathyroidism,
  nutritional osteopathies (rare)
• Benign familial hyperphosphatasemia
• Siberian huskies

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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 Cushings (95)
• Very poor specificity (18)

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Liver Alkaline Phosphatase

• Located predominantly in the periportal zone
• Bile canaliculi and sinusoidal membranes
• L-ALP is predominate isoenzyme in dogs gt1 yr
• Two mechanisms for increase
• Cholestasis
• Drug induction
• Phenobarbital
• Exogenous steroids

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Differentials for increased ALP

• B-ALP
• Young animals, bone neoplasia, nutritional
  osteopathy, hyperparathyroisim
• C-ALP
• Cushings, 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

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Common conditions causing only increased ALP

• Cushings disease
• Drug induction
• Idiopathic vacuolar hepatopathy
• Hepatic neoplasia
• Nodular hyperplasia
• Breed-related

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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.)

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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

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The diagnostic dilemma begins

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

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Questions to ask yourself

• What is the patients age and breed?
• What medications is the patient on?
• Topicals and inhaled
• WHY was the blood work performed?
• Is the elevation repeatable?

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More questions to ask

• Any clinical signs of Cushings dz?
• Before the blood work was performed?
• Other biochemical changes?
• Hepatic, biliary or pancreatic disease?
• Does the patient have any evidence of systemic
  illness?

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Beyond a CBC, Chemistry and UA

• Abdominal ultrasound
• Endocrine testing
• Urine cortisolcreatinine ratio
• LDDS
• ACTH stimulation test
• Tennessee adrenal panel
• Bile acids
• Liver aspirate/biopsy
• Valley Fever titer???
• Thoracic radiographs???

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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

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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

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Rainy Bates 9 yr FS Aussie mix

• What is the patients 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

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Rainy Bates 9 yr FS Aussie mix

• Any clinical signs of Cushings dz?
• YES!
• Other biochemical changes?
• No
• Does the patient have any evidence of systemic
  illness?
• No

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Rainy Bates 9 yr FS Aussie mix

• Abdominal ultrasound
• Bilateral enlarged adrenal glands
• Homegenously enlarged liver
• ACTH stimulation
• Consistent with Cushings Dz go figure
• Lysodren therapy
• ALP 245 U/L

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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

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Fionna 8 yr FS Scottish Terrier

• What is the patients 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

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Fionna 8 yr FS Scottish Terrier

• Are there any clinical signs of Cushings
  disease?
• ???
• Are there other biochemical changes suggestive of
  hepatic, biliary or pancreatic disease?
• No
• Does the patient have any evidence of systemic
  illness?
• No

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Next step?

• UA
• USG 1.020
• No proteinuria
• Abdominal ultrasound
• WNL
• ACTH stimulation
• Pre 7 Post - 18
• Bile acids
• WNL

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Liver Biopsy

• Vacuolar hepatopathy

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More???

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

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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

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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 Cushings disease

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Rusty Hughes 4 yr MN Labrador

• What is the patients 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 Cushings
• Is the elevation repeatable?
• Yes

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Rusty Hughes 4 yr MN Labrador

• Are there any clinical signs of Cushings
  disease?
• Yes
• Are there other biochemical changes suggestive of
  hepatic, biliary or pancreatic disease?
• ???
• Does the patient have any evidence of systemic
  illness?
• Yes

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Rusty Hughes 4 yr MN Labrador

• Abdominal ultrasound
• Enlarged and uniformly hyperechoic liver
• Gallbladder WNL
• Further plan?
• Taper off of steroids and phenobarbital!

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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

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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

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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)

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Zoe Marsh 9 yr FS Lhasa Apso

• Whats the patients 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?
• Yesand increasing

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Zoe Marsh 9 yr FS Lhasa Apso

• Are there any clinical signs of Cushings
  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

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Plan???

• ACTH stim?
• Bile Acids?
• Liver Bx?

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What I did

• Total T4 WNL
• Repeat abdominal ultrasound

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Surgery???

• Cholecystectomy Bile culture Liver biopsy
• Bile culture
• Negative
• GB histopathology
• Biliary mucocele
• Liver histopathology
• Mild-moderate vacuolar hepatopathy

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Follow-up

• Continued ursodiol
• ALP 2 months after surgery
• 345 U/L

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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

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Roxy Milho 10 yr FS Rottie mix

• Whats the patients 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?
• ???

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Roxy Milho 10 yr FS Rottie mix

• Are there any clinical signs of Cushings
  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

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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

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QUESTIONS???