ALP is one of the most important liver enzymes we monitor on blood screens of our canine patients. It is the most commonly elevated liver enzyme and also the least liver-specific enzyme. ALP stands for Alkaline phosphatase and is an enzyme that is bound to the membranes of the bile ducts within the liver. An isoform of this enzyme is also present in bone. When there is congestion or swelling of the liver this enzyme value will rise. This enzyme will also rise when there is increased bone activity. Not all ALP elevations represent a serious issue. It takes some detective work to figure out which ALP elevations could mean trouble is brewing. Although reference ranges can vary, most normal ALP values in dogs are between 5-131 U/L.
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Not all alkaline phosphatase enzyme elevations are serious in dogs
It is commonplace to see mild ALP elevations in older dogs due to normal aging changes to the liver. A “normal aging” change in older dogs is an ALP rise of no more than 2-3 times the upper end of the normal range. ALP elevations are expected in puppies under 15 months of age as they are growing and their skeleton is maturing. In fact, over 70% of dogs under the age of one have an ALP greater than >150u/L. ALP elevations less than 2 times the upper limit of normal in a dog less than 15 months is considered normal. ALP should start to decline by 12 weeks of age and be normal by 15 months of age. However, a more serious disease cannot be ruled out in dogs with a mild ALP elevation. The tricky part is determining when an ALP elevation is significant.
So, how do we know when an elevation in ALP represents a problem, especially in a normal dog?
Routine blood screening of over a 1000 dogs identified that 39% had elevations in ALP. If ALP is the only liver enzyme elevated, and the increase is LESS than 3 times the upper reference range limit, chances are much less likely that this represents something sinister.
Common conditions associated with only an elevation of ALP alone are: Cushing’s, idiopathic vacuolar hepatopathy, hepatic nodular hyperplasia , drug induction of ALP (such as steroids and phenobarbital), breed related disorders and liver tumors .
For mild elevations in ALP, a bile acids assay can be used to directly test liver function. Another option is to monitor the liver values with a repeat serum chemistry in 4 weeks. If the enzyme is not increasing, serial monitoring at regular intervals is recommended. If the value continues to rise and/or other liver related enzymes start to rise, then further investigation may be warranted.
Why does ALP rise in dogs?
Swelling and congestion within the liver will cause increased production of ALP and release of this enzyme into the bloodstream. Cholestasis is the term used for reduction of flow of bile through channels in the liver. Enzyme markers for cholestasis are ALP and GGT (the two membrane bound enzymes on the biliary surface).
Hepatobiliary disease (disease of the liver and bile channels in the liver) is more likely when ALP and GGT are elevated. Only 50% of dogs have hepatobiliary disease with just an elevation in ALP. However, when ALP and GGT are elevated,over 90% of patients will be diagnosed with hepatobiliary disease. There are other disease processes (extrahepatic disease) that can cause congestion and mild liver swelling.
Six main categories for ALP elevations in dogs:
- Age and breed: (dogs under the age of 15 months) due to skeletal maturation . Breed related conditions have associated ALP elevations (seen in Siberian Huskies with familial hyperphosphatasemia and Scottish terriers).
- Drug- induced ALP elevation (steroids, phenobarbital are common drugs implicated )
- Cushing’s disease. This endocrine disease causes excess production of a natural steroid in the body.
- Primary liver disease : vacuolar hepatopathy, cholangitis, hepatitis, nodular hyperplasia and cancer
- Systemic disorders causing a reactive hepatopathy. Physiologic stress associated with chronic illness (cancer, infection, inflammation, GI disease, endocrine disease such as Diabetes mellitus, hypothyroidism) cause reactive liver changes.
- Bone related disorder (cancer, nutritional bone disease, hyperparathyroidism secondary to kidney die)
Liver enzyme elevations in dogs not due to liver disease
Disease unrelated to the liver (extra-hepatic conditions) can also cause cholestatic enzymes to rise. Extra-hepatic conditions can cause increased lipid and glycogen storage in the liver. When the liver stores excess lipid and glycogen in the liver cells, the liver swells and causes ALP and GGT to rise. Extrahepatic causes of liver enzyme elevations include: Cushing’s disease, diabetes mellitus, hypothyroidism, pancreatitis and inflammation in the bowel. Certain cancers like mammary cancer, pancreatic cancer and bone tumors can over-express the alkaline phosphatase enzyme.
Drugs that raise ALP in dogs:
Drugs that are well known to boost ALP production by the liver are most commonly anti-seizure medications (phenobarbital and primidone) and steroids. The use of steroids raises ALP to variable degrees depending on the formulation and dose. A single injection of methylprednisolone has been shown to cause ALP to increase for up to 3 weeks after the single injection. Eye drops containing steroids and routine use of steroid containing ointments or sprays may be systemically absorbed and influence ALP production.
Cushing’s disease in dogs raises ALP
Cushing’s is an endocrine disease caused by the adrenal glands overproducing a natural steroid hormone. ALP values may be as high as 100 times higher than normal. ALP elevation occurs in over 80% of dogs with Cushing’s disease.
The hallmark of Cushings’ disease is an elevated ALP on screening blood work. However, Cushing’s disease requires a battery of confirmatory tests to definitely diagnose. Typical clinical findings for cushing’s disease are: increased thirst and urination ( pu/pd), increased hunger, panting, a pendulous abdomen, thinning coat along the trunk , and thinning skin.
Breed related ALP increases in Siberian Huskies and Scottish Terriers
Some Siberian Huskies have a temporarily elevated ALP that is genetic. Their ALP’s can measure up to 5 items higher than an unaffected puppy. This enzyme will start to go down after 16 weeks of age and has no clinical consequences.
Scottish Terriers can also have a familial form of hyperphosphatasemia. They have persistently elevated ALP levels up to 5 times higher than other breeds. This is thought to be due to a form of adrenal dysfunction. They produce the corticosteroid induced isoform of ALP and the condition.
ALP elevations in dogs secondary to cancers in the liver and not in the liver
ALP elevations in dogs with diagnosed bone tumors is a negative prognostic indicator. A value>120U/L has been associated with a poor prognosis. The ALP elevation indicates that bone cancer is more rapidly proliferative.
Mammary tumors (both benign and malignant) have been associated with an increase in ALP (median 170U/L, range 50-to 4880 U/L) and is of no prognostic value in determining benign versus malignant mammary cancer in a dog.
Canine hepatocellular carcinoma causes a unique expression of an isoenzyme of ALP.
Pancreatic cancer can also induce ALP and GGT expression.
Additional tests to determine the significance of liver enzyme elevations in a dog
Elevations in ALP and/or GGT are highly sensitive for hepatobiliary disease. Other tests to evaluate hepatic function include measurement of serum bilirubin, ammonia , albumin, glucose, cholesterol and total serum bile acid concentrations. The liver synthesizes cholesterol and the protein albumin. It also makes glucose from stored glycogen reserves. Glucose, cholesterol, albumin and bilirubin are all commonly chemistry values on a blood screen. Bilirubin , if elevated, implies that the liver is not functioning properly to handle bile acids. However, if the bilirubin is normal, a bile acids test would need to be performed to investigate liver function.
Imaging of the liver in your dog
Imaging of the liver with an x-ray provides limited information. It mostly screens for the size and shape of the liver. Sometimes stones in the gallbladder can be recognized. A more useful non invasive method to image the liver is with an abdominal ultrasound exam. An ultrasound can be performed on an awake patient. It provides information about the size of the liver and the character of the liver tissue. An ultrasound can determine if there are masses within the liver, signs of scarring, nodules, or if the tissue looks bright or dull. These all provide clues as to what may be happening in the liver.
For example, steroid hepatopathy and hepatic lipidosis both have hyperechoic (bright) liver changes on ultrasound. Gallbladder mucocoeles, stones in the gallbladder and bile duct dilation can be identified readily on ultrasound. Hepatic portal vasculature can be examined to identify liver shunts. An abdominal ultrasound exam can also support the diagnosis of Cushing’s disease by measuring enlarged adrenal glands. Pancreatitis can be diagnosed as can GI disease by identifying thickened layers of bowel on the ultrasound.
When to perform a liver biopsy on a dog
If imaging does not show any abnormalities that dictate a specific diagnosis (gb mucocele, gall bladder stone, liver shunt) then consider a liver biopsy sample.
Biopsies of the liver can provide the most valuable information about what may be infiltrating the liver. It can help determine if the liver enzyme elevations are secondary to benign increases in liver storage of glycogen. Biopsies can detect chronic inflammation (hepatitis), fibrosis of the liver (cirrhosis) or cancer. Liver biopsies with a fine needle or a trucut biopsy are commonly performed because they are less invasive and don’t require anesthesia. The best biopsies are surgical biopsies which provide the most tissue to examine. The best course of action should be discussed with your veterinarian.
Common benign liver changes that can raise ALP in dogs
At our hospital we perform about 10-30 abdominal ultrasounds a day by our radiology department. Countless older dogs have liver changes on ultrasound consistent with benign nodular or vacuolar hepatopathy. This is a liver change that causes scattered nodules or bumps within the liver that are a little darker in color compared to the color of the rest of the liver. It is considered a normal aging change in dogs. Unfortunately they cannot be absolutely distinguished from inflammatory liver disease (hepatitis) , liver cirrhosis, or even some infiltrative liver cancers. Imaging findings have to be paired with exam findings, blood work changes, and whether your dog feels well or unwell.
For example, a senior dog who has no abnormal symptoms and mild liver enzyme elevations will more likely have benign liver changes like nodular hepatopathy. A dog with evidence of liver failure on labwork ( elevated bile acids, low blood glucose and low albumin, elevated liver enzymes) and who is feeling ill will be interpreted to have serious liver disease with the same ultrasound findings.
How to determine the significance of elevated liver enzymes in your dog
Veterinarians have to determine the significance of a high ALP value. To assess significance we pair results with cues from our patient’s history, physical exam findings, age and breed.
Patient history that may explain liver enzyme elevations in your dog:
Determine if there is any access to potentially hepatotoxic drugs, supplements or nutraceuticals.
Ask about exposure to environmental toxins or infectious agents, any recent anesthesia, and the vaccination status of the dog.
Determine if there are symptoms of underlying disease such as vomiting, diarrhea, weight loss, increased thirst/urination, behavior changes, exorcise intolerance.
Well known possible toxic causes of acute liver injury in the dog
- Aflatoxins in corn, nuts other food products
- xylitol
- Cycad palm plant
- Sulfonamide drugs (can be in antibiotic or dewormer)
- Mitotane
- amiodarone
- Iron
- Acetaminophen
- Blue green algae
Physical exam findings that may indicate underlying illness associated with liver enzyme changes in your dog
- poor coat quality
- thin skin
- palpable cranial abdominal enlargement
- pot bellied appearance
- poor body condition
- poor growth (liver shunt)
- abdominal discomfort (pancreatitis)
- palpably thickened intestines (IBD)
Signalment (age, breed) that can fit with liver diseases in dogs:
Breed related hepatopathy can occur in the: Bedlington terrier, cocker spaniel, dalmatian, Doberman pinschers, Labrador retrievers, Skye terrier, West Highland white terriers.
Portosystemic liver shunts have breed associations in Miniature schnauzers and Yorkshire terriers.
Summary of the significance of an elevated alkaline phosphatase in a dog
Further testing is warranted if there are liver enzyme elevations in any dog who is a breed predisposed to hepatopathy. If your dog has no history of drug exposure that could cause acute liver changes, or if your dog has an elevation greater than 3 times the upper reference range limit in more than one liver enzyme then do further testing. Other lab work cues are: progressive increase in enzyme activities, or a single enzyme elevation AND an increase in bilirubin OR decrease albumin concentration. Although ALP elevations are commonplace in dogs, the good news is the majority of cases are benign.
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