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Alkaline Phosphatase (ALP)

Alkaline phosphatase (ALP) refers to a family of enzymes that catalyze hydrolysis of phosphate esters at an alkaline pH. ALP is present (in decreasing order of abundance) in placenta, intestine, kidney, bone and liver. In adults, more than 80% of serum ALP activity derives from liver and bone. In late pregnancy, placental ALP is increased. In children and adolescents, most plasma ALP activity originates in osteoblasts and correlates with the rate of bone growth. Plasma half‑life is seven days.

Several caveats must be remembered in interpreting ALP results:

  • ALP levels should always be measured after fasting because enzyme levels increase as much as 30 U/L after food ingestion.
  • Patients with blood group O and B who are secretors can have increased ALP levels after eating a fatty meal because of the release of intestinal enzyme.
  • African Americans have 10 to 15% higher ALP serum levels than Caucasians.
  • In children, ALP is increased up to 3 times the upper limit of normal and in pregnant patients it can be increased up to 2 times normal.
  • ALP levels may double following bone fracture.
  • Smokers have 10% higher ALP levels than nonsmokers do.
  • ALP levels fluctuate approximately 6% from week to week in a healthy individual.

ALP is most useful in diagnosing cholestatic liver diseases. Bile duct obstruction results in increased synthesis of ALP by bile duct epithelial cells and release of ALP into the serum. Alkaline phosphatase may be increased even if only a few small bile ducts are obstructed, and serum bilirubin is normal. Serum ALP often exceeds four times the upper limit of normal in extrahepatic and intrahepatic cholestasis. The most common causes of extrahepatic cholestasis are pancreatic cancer, common duct stones and strictures, and primary sclerosing cholangitis. Intrahepatic cholestasis is usually due to primary biliary cirrhosis or drug reactions (erythromycin, chlorpromazine, estrogens, and methyltestosterone). Patients with primary sclerosing cholangitis and primary biliary cirrhosis initially have elevated ALP and normal bilirubin levels.

When the ALP level is increased disproportionately to the bilirubin level (e.g. a bilirubin <1.0 mg/dL and ALP >1000 U/L), granulomatous or infiltrative diseases of the liver are likely. Possible diagnoses include sarcoidosis, fungal infections, tuberculosis, and lymphoma. ALP levels are also increased in hyperthyroidism, cardiac failure, lymphoma, and hypernephroma.

Lower ALP levels (<3 times the upper limit of normal) are less specific for cholestatic liver disease and may be seen with hepatocellular diseases such as acute viral hepatitis, chronic hepatitis, and cirrhosis. However, it is important to remember that incomplete obstruction by gallstones may produce mildly elevated ALP levels. Intrahepatic cholestasis secondary to anabolic steroids or birth control pills may cause mild increases in ALP. Gamma glutamyltransferase (GGT) can be measured to determine if elevated ALP levels are of liver origin; increased GGT indicates that ALP is most likely from the liver.

Medications that have been reported to increase ALP include; allopurinol, anabolic steroids, captopril, carbamazepine, chlorpromazine, chlorpropamide, diltiazem, erythromycin, estrogens, flutamide, gold salts, methimazole, methyltestosterone, phenothiazines, phenylbutazone, phenytoin, quinidine, sulfonamides, tolazamide, tolbutamide, trimethoprim-sulfamethoxazole, valproic acid, and verapamil.

Sometimes it is useful to look at the relationship of ALP to bilirubin and lactate dehydrogenase (LD) levels.

Pathology ALP Bilirubin LD
Intra or extrahepatic cholestasis Increased Increased Normal
Focal benign cholestasis Increased Normal Normal
Focal malignant cholestasis Increased Normal Increased


Osteoblastic bone disease can also increase serum ALP. The most common bone disorders associated with elevated ALP are; Paget’s disease, osteomalacia, hyperparathyroidism, osteogenic sarcoma, and bone metastases.

Physicians are usually concerned about elevated plasma enzyme levels. Occasionally, clinical laboratories report enzyme results that are below the lower end of the reference range. An older publication examined the causes for low serum alkaline phosphatase (ALP) activity in a large Veterans Medical Center. One hundred and thirty of 69,864 ALP results (0.19%) from 88 individual patients made over a 4-year period were less than 30 U/L. Eighty three of the 88 individuals’ medical charts were reviewed for potential causes of the low ALP results. The most commonly identified causes of low ALP concentration in a predominantly male population were cardiopulmonary bypass surgery, malnutrition, magnesium deficiency, hypothyroidism and severe anemia. Decreases in both ALP and magnesium observed in the postcardiac surgery patients appeared to be a consequence of cardiopulmonary bypass and not hemodilution alone. Magnesium is a cofactor for ALP activity, but the addition of magnesium to serum samples from postoperative cardiac surgery patients did not restore ALP activity, suggesting that something other than magnesium was affected by cardiopulmonary bypass.

Other causes of low ALP that have been reported in the medical literature include:

  • Hypophosphatasia
  • Hypoparathyroidism
  • Zinc deficiency
  • Vitamin D toxicity
  • Collection of blood in EDTA blood collection tubes
  • Pernicious anemia
  • Estrogen replacement therapy in postmenopausal women
  • Wilson's disease
  • Hepatic resection and transplantation
  • Celiac disease
  • Achondroplasia and hypothyroidism in children
  • Chronic renal osteodystrophy causing osteopenia
  • Vitamin C deficiency

Low plasma ALP level returns to normal after thyroid replacement therapy. Pernicious anemia is associated with cobalamin deficiency. Cobalamin deficiency is associated with lower ALP concentrations because osteoblast activity is dependent on cobalamin. Low ALP activity during estrogen replacement therapy for postmenopausal women with osteoporosis is attributed to inhibition of bone resorption by estrogen.

Reference range in adults is 40 - 125 IU/L (Vitros Analyzer).

Specimen requirement is one SST tube of blood. If blood is collected in a citrate or EDTA tube, ALP activity will be almost totally inhibited due to the chelation of zinc and magnesium, which are necessary enzyme cofactors.


Lum G. Significance of low serum alkaline phosphatase activity in a predominantly adult male population. Clin Chem. 1995 Apr;41(4):515-8).

Agganis B, Lee D and Sepe T. Liver Enzymes: No trivial elevations, even if asymptomatic. Cleveland Clinic J Med 2018;85:612-17.

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