Alkaline phosphatase (ALP) is a group of closely related enzymes with maximal activity when the pH is about 10. ALP is found in many tissues, with highest concentrations in liver and biliary tract epithelium, bone, intestinal mucosa, and placenta. Liver and bone are the two tissues most commonly responsible for ALP elevation. ALP is composed of several isoenzymes, and each of the major sources of ALP contains a different isoenzyme. Reference range values are about 1.5-2.0 times higher in children than in adults due to active bone growth. Even higher levels occur during the adolescent “growth spurt,” which occurs in girls aged 8-12 years and boys aged 10-14 years. Peak reference values for adolescents are reported to be 3-5 times adult values, although occasional persons are said to have values as high as seven times the adult upper reference range. Three times the adult reference range is more typical in my experience. Adult values were reported in girls by age 16 and in boys at approximately age 20.

Alkaline phosphatase of liver origin

In liver, ALP is formed by liver cells and biliary tract mucosal cells. It is excreted into bile through a different mechanism from that controlling bilirubin excretion. Although ALP of liver origin can be increased in serum during any type of active liver disease, the serum level is especially sensitive to biliary tract obstruction, whether intrahepatic or extrahepatic, whether mild or severe, or whether localized in a small area of the liver or more extensive. As a general rule, the degree of ALP elevation reflects the severity of obstruction and the amount of biliary tissue involved. Unfortunately, there is considerable variation in behavior of ALP among individual patients.

Common etiologies for ALP elevation are listed in the box. The three liver conditions most frequently associated with ALP elevation are extrahepatic (common bile duct) biliary tract obstruction, intrahepatic biliary tract obstruction due to acute liver cell injury, and liver space-occupying lesions (tumor, abscess, granulomas). Common bile duct obstruction, metastatic tumor to the liver, and the uncommon condition of primary biliary cirrhosis are the most frequent etiologies for persistent ALP elevation more than 3 times the upper reference limit. However, metastatic tumor may be present with lesser degrees of elevation or with no elevation. On the other hand, acute liver cell injury occasionally may produce ALP elevation more than 3 times the upper reference limit. In one or more reports, ALP elevation 5 times the upper reference limit or more occurred in 5% of patients with hepatitis virus hepatitis, 13%-20% of those with infectious mononucleosis, and 5% of persons with active alcoholic cirrhosis. Drug-induced liver dysfunction is another consideration.

Most Common Causes for Alkaline Phosphatase Elevation

Liver and biliary tract origin
Extrahepatic bile duct obstruction
Intrahepatic biliary obstruction
Liver cell acute injury
Liver passive congestion
Drug-induced liver cell dysfunction
Space-occupying lesions
Primary biliary cirrhosis
Sepsis
Bone origin (osteoblast hyperactivity)
Physiologic (rapid) bone growth (childhood and adolescent)
Metastatic tumor with osteoblastic reaction
Fracture healing
Paget’s disease of bone
Capillary endothelial origin
Granulation tissue formation (active)
Placental origin
Pregnancy
Some parenteral albumin preparations
Other
Thyrotoxicosis
Benign transient hyperphosphatasemia
Primary hyperparathyroidism

In metastatic carcinoma to the liver, ALP levels are elevated in about 75%-80% of cases (literature range, 42%-100%). ALP levels are also elevated in hepatoma, liver abscess, liver granulomas, and other active liver space-occupying lesions. The frequency of ALP elevation is not as well documented in these conditions as in metastatic tumor but apparently is similar. In extrahepatic biliary tract (common bile duct) obstruction or in primary biliary cirrhosis, ALP levels are elevated in nearly 100% of patients except in some cases of incomplete or intermittent obstruction. Values are usually greater than three times the upper reference range limit, and in the most typical cases exceed 5 times the upper limit. Elevation less than 3 times the upper limit is some evidence against complete extrahepatic obstruction. In patients with jaundice due to intrahepatic obstruction (most often severe active cirrhosis or hepatitis virus hepatitis), ALP levels are usually elevated and can exhibit a wide range of values. Most often the levels are less than 3 times the upper reference limit, but 5%-10% of patients have a greater degree of elevation. In nonjaundiced patients with active liver cell damage, ALP levels are elevated in about one half of the cases, usually less than 3 times the upper reference limit. Inactive cirrhosis or uncomplicated mild fatty liver usually does not result in ALP elevation. Fifteen percent to 20% of patients with infectious mononucleosis have ALP values greater than 3 times normal, even though liver biopsy shows relatively mild liver changes. Alkaline phosphatase levels are elevated in about 10%-20% of patients with liver passive congestion, with values usually less than twice normal. It may be higher in a few patients.

Alkaline phosphatase of bone origin

Sources other than the liver can elevate serum ALP levels either alone or concurrently with liver source ALP elevation. Bone is by far the most frequent extrahepatic source. Osteoblasts in bone produce large amounts of ALP, and greatly increased osteoblastic activity hinders usefulness of ALP determination as a liver function test. Normal bone growth of childhood and adolescence, healing fractures, Paget’s disease of bone (85% of cases in early stage; 100% later), hyperparathyroidism, rickets and osteomalacia, and osteoblastic metastatic carcinoma to bone all consistently produce elevated values. In a patient with jaundice, however, one can surmise that at least a portion of an ALP elevation is due to liver disease.

When doubt exists as to the origin of the increased ALP values, several alternatives are available. One possibility is use of another enzyme that provides similar information to ALP in liver disease but is more specific for liver origin. Enzymes that have been widely used for this purpose are 5′-nucleotidase (5-NT) and gamma-glutamyltransferase (GGT). Of these, the methodology of 5-NT is probably a little too difficult for reliable results in the average laboratory; also, according to at least one report, about 10% of patients with bone disease may display slight elevation. The GGT has sensitivity equal to or greater than ALP in obstructive liver disease and greater sensitivity in hepatocellular damage. Various reports in the literature state that the GGT level is not elevated in bone disease. However, some data in these reports suggest that GGT may occasionally be mildly elevated in bone disease. Another method for differentiating tissue origin of ALP is isoenzyme separation of specific ALP bone and liver fractions by the use of heat, chemical, enzymatic, or electrophoretic techniques. Of these, electrophoresis is the most difficult but probably the most reliable and informative.

Other sources of alkaline phosphatase elevation

In pregnancy, the placenta produces ALP; ALP of placental origin begins to rise at about the end of the first trimester and can reach values up to 4 times the upper reference limit in the third trimester. However, the pregnancy-related increase in ALP also has a bone-derived component, with placental ALP comprising about 60% of total serum ALP in the second and third trimesters. Placental ALP has a half-life of about 7 days and in most patients is gone by 3-6 days after delivery. Bone-derived ALP is longer-lived and can persist even more than 6 weeks after delivery. However, only a very few patients have an elevated ALP level from pregnancy alone that persists more than 4 weeks postpartum. In 100 consecutive patients in our hospital at time of delivery, 15% had an ALP level within reference range, 50% had elevated ALP between 1-2 times the upper normal limit, 29% had values between 2-3 times the upper limit, and 6% had values between 3-4 times the upper limit.

Certain persons whose blood belongs to group B or O and secrete ABH substance are reported to show an increase of ALP (of intestinal isoenzyme origin) about 2 hours after a fatty meal. ALP levels may become elevated following therapeutic administration of albumin, since some companies use placental tissue as the source for their albumin. ALP levels can become elevated 7-14 days after severe tissue damage or infarction due to ALP produced by fibroblasts and endothelial cells proliferating in new granulation tissue. ALP levels are reported elevated in 42%-89% of patients with hyperthyroidism. In one report, about half had elevation in both the bone and liver isoenzyme. The remainder had elevation either of bone or liver fraction. The bone fraction usually increases after therapy of hyperthyroidism and can remain elevated for a long time. Certain medications that may affect the liver (see Table 37-2; XIV) may sometimes be associated with ALP elevation. The most frequent of these is phenytoin (Dilantin). ALP levels are elevated in about 40%-50% (range, 22%-63%) of patients taking phenytoin, with values in most cases not exceeding twice the upper reference limit. Elevation of ALP has been reported in a few patients with sepsis.

Benign transient hyperphosphatasemia usually occurs in young children, but can occur in older children and rarely even in adults. Patients are reported to have a variety of illnesses, including infection, but no one condition heavily predominates as a possible cause. The ALP level is usually more than 5 times the upper adult limit (which calls attention to the patient) and frequently is considerably higher than that. The ALP level usually returns to reference range in 2-4 months but occasionally elevation persists longer. Various ALP isoenzyme patterns have been reported, including bone only, liver only, and more commonly, bone plus liver or bone plus liver plus a third isoenzyme migrating next to liver between bone and liver.