ALP catalyzes the alkaline hydrolysis of a wide variety of natural and synthetic substrates. This enzyme is present in many organs and is especially associated with cell surfaces located in the mucosa of the small intestine and in the proximal convoluted tubules of the kidney, in bone (osteoblasts), in the liver and in the placenta, anchored on the cell mem brane by glycosylphosphatidylinositol (ectoenzyme). Although its exact metabolic function is not yet understood, it appears that ALP is associated with lipid transport in the intestine and with the calcification process in bone.

ALP exists in multiple forms (molecular weight 70–120 kDa), some of which are true isoenzymes, encoded by separate genetic loci. Bone, liver, and kidney forms of ALP share a common primary structure, encoded by the same genetic locus, but differ in carbohydrate content. The ALP activity present in the sera of apparently healthy adults comes primarily from the liver, with most of the remaining activity coming from the bone. The relative contributions of these two forms of the enzyme to total ALP activity are age dependent. Minimal amounts of intestinal ALP may also be present, particularly in the sera of individuals of blood group B or 0 (secretory subjects). Because intestinal ALP activity in serum may increase after a meal, ALP should preferably be measured in fasting state.

Clinical Significance Increases in serum ALP activity commonly come from two major sources: liver and bone. Consequently, the measurement of serum ALP is of particular interest in the study of two groups of conditions: hepatobiliary diseases and bone diseases associated with the increased osteoblastic activity.

The liver’s response to any form of biliary tree obstruction induces ALP synthesis by hepatocytes. The newly formed ectoenzyme is released from the cell membrane by the action of bile salts and enters the circulation by increasing enzyme activity in the serum. Increases tend to be greater (4 × URL) in extrahepatic obstruction (from gallstones or pancreatic head cancer) than in intrahepatic obstruction and are greater the more complete the obstruction. Enzyme activity can reach 10–12 times the URL and usually returns to baseline following surgical removal of the obstruction. Increased ALP (>2 × URL) can predict disease outcome (liver transplantation or death) in patients with primary biliary cirrhosis.

Liver diseases that primarily affect parenchymal cells, such as infectious hepatitis, typically show only moderately increased (<3 × URL) or even normal serum ALP activities. Increases could also be a side effect of drug therapy, and criteria based on the measurement of ALT and ALP have been recommended to discriminate the type of liver injury in drug- induced toxicity (Table 1). The intestinal isoenzyme of  ALP, an asialoglycoprotein normally picked up by specific hepatic receptors, is often increased in patients with liver cirrhosis.

Table 1. Criteria for drug-induced liver toxicity based on enzymatic data according to the Council of International Organizations of Medical Sciences (1990)^a

An increase of up to two to three times the URL due to the placental-derived enzyme is observed in women in the third trimester of pregnancy. This makes ALP an unreliable marker of hepatobiliary disease in pregnancy. Benign familial increases in serum ALP levels due to increased intestinal ALP concentrations have also been described. Transient, benign increases in serum ALP may be observed in infants and children, with changes often >10 times the URL. These changes appear to reflect a reduction in blood ALP clearance caused by transient changes in glycosylation of the enzyme. Tissue-specific ALP gene mutations are associated with hypophosphatasia, a rare inherited disorder characterized by poor bone mineralization and low serum ALP concentrations.

Reference Intervals

Serum ALP activity varies with age and sex. Infants and children show higher ALP activity than healthy adults because of bone ALP production by osteoblasts during bone growth. However, activities in growing children are highly variable and it is known that the decrease in ALP activity to typical adult values differs from subject to subject, occurring on average 2 years earlier in females than in males.

In adult individuals, the following reference intervals have been established: 33–98 U/L for females of childbearing age and 43–115 U/L for males. A progressive increase in enzyme values is described for women after menopause.