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Subject: Alkaline Phosphatase (ALP)
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ALP refers to a family of enzymes that catalyze hydrolysis of phosphate esters at an alkaline pH. There are at least five isoenzymes derived from the liver (sinusoidal and bile canalicular surface of hepatocytes), bone, intestine (brush border of mucosal cells), placenta, and tumor-associated tissues separated by electrophoresis. Placenta and tumor-associated ALP are the most heat resistant to inactivation. More than 95% of total ALP activity comes from the bone and liver (approximately 1:1 ratio). The half-life of ALP is 7–10 days.
0–1 year: 150–350 IU/L
1–16 years: 30–300 IU/L
>16 years: 30–115 IU/L
Diagnosis and treatment of the liver, bone, intestinal, and parathyroid diseases
Increased bone formation
Bone diseases (metastatic carcinoma of the bone, myeloma, Paget disease)
Renal disease (renal rickets due to vitamin D–resistant rickets associated with secondary hyperparathyroidism)
Liver disease (e.g., infectious mononucleosis, uncomplicated extrahepatic biliary obstruction, liver abscess)
Miscellaneous (extrahepatic sepsis, ulcerative colitis, pancreatitis, phenytoin, and alcohol use)
Bone origin—increased deposition of calcium
Paget disease (osteitis deformans) (highest reported values 10–20 times normal). Marked elevation in the absence of liver disease is most suggestive of Paget disease of bone or metastatic carcinoma from the prostate.
Increase in cases of metastases to bone is marked only in prostate carcinoma.
Osteoblastic bone tumors (osteogenic sarcoma, metastatic carcinoma).
Osteogenesis imperfecta (due to healing fractures).
Polyostotic fibrous dysplasia.
Late pregnancy; reverts to normal level by 20th day postpartum.
Children <10 years of age and again during prepubertal growth spurt may have three to four times adult values; adult values are attained by age 20.
Administration of ergosterol.
Transient hyperphosphatasemia of infancy
Healing of extensive fractures (slightly).
Any obstruction of the biliary system (e.g., stone, carcinoma, primary biliary cirrhosis) is a sensitive indicator of intrahepatic or extrahepatic cholestasis. Whenever the ALP is elevated, a simultaneous elevation of 5′-nucleotidase (5′-N) establishes biliary disease as the cause of the elevated ALP. If the 5′-N is not increased, the cause of the elevated ALP must be found elsewhere (e.g., bone disease).
Liver infiltrates (e.g., amyloid or leukemia)
Cholangiolar obstruction in hepatitis (e.g., infectious, toxic)
Hepatic congestion due to heart disease
Adverse reaction to therapeutic drug (e.g., chlorpropamide) (progressive elevation of serum ALP may be first indication that drug therapy should be halted); may be 2–20 times normal
Increased synthesis of ALP in the liver
Diabetes mellitus—44% of diabetic patients have 40% increase of ALP.
Parenteral hyperalimentation of glucose.
Liver diseases with increased ALP
Less than three to four times increase lacks specificity and may be present in all forms of liver disease.
Two times increase: acute hepatitis (viral, toxic, alcoholic), acute fatty liver, cirrhosis.
Two to ten times increase: nodules in the liver (metastatic or primary tumor, abscess, cyst, parasite, TB, sarcoid); is a sensitive indicator of a hepatic infiltrate.
Increase more than two times the upper limit of normal in patients with primary breast or lung tumor with osteolytic metastases is more likely caused by liver than by bone metastases.
Five times increase: infectious mononucleosis, postnecrotic cirrhosis.
Ten times increase: carcinoma of the head of the pancreas, choledocholithiasis, and drug cholestatic hepatitis.
Fifteen to twenty times increase: primary biliary cirrhosis, primary or metastatic carcinoma. The GGT-to-ALP ratio >2.5 is highly suggestive of alcohol abuse.
Chronic therapeutic use of anticonvulsant drugs (e.g., phenobarbital, phenytoin).
Placental origin: appears at 16th–20th week of normal pregnancy, increases progressively to two times normal up to onset of labor, and disappears 3–6 days after delivery of placenta. ALP may be increased during complications of pregnancy (e.g., hypertension, preeclampsia, eclampsia, threatened abortion) but is difficult to interpret without serial determinations. It is lower in diabetic than in nondiabetic pregnancy.
Intestinal origin: is a component in approximately 25% of normal sera; increases 2 hours after eating in persons with blood type B or O who are secretors of the H blood group. ALP has been reported to be increased in cirrhosis, various ulcerative diseases of the GI tract, severe malabsorption, chronic hemodialysis, and acute infarction of the intestine.
Benign familial hyperphosphatasemia.
Ectopic production by neoplasm (Regan isoenzyme) without involvement of the liver or bone (e.g., Hodgkin disease; cancer of the lung, breast, colon, or pancreas; highest incidence in ovary and cervical cancers).
Vascular endothelium origin—some patients with myocardial, pulmonary, renal (one third of cases), or splenic infarction, usually after 7 days during the phase of organization.
Hyperphosphatasia (liver and bone isoenzymes).
Hyperthyroidism (liver and bone isoenzymes). Increased ALP alone in a chemical profile, especially with a decreased serum cholesterol and lymphocytosis, should suggest excess thyroid medication or hyperthyroidism.
Primary hypophosphatemia (often increased).
ALP isoenzyme determinations are not widely used clinically; heat inactivation may be more useful to distinguish bone from liver source of increased ALP (extremely Ninety percent heat-labile: bone, vascular endothelium, reticuloendothelial system; extremely 90% heat-stable: placenta, neoplasms; intermediate 60–80% heat stable: liver, intestine). Also differentiate by chemical inhibition (e.g., l-phenylalanine) or use serum GGT, leucine aminopeptidase.
Children—mostly bone; little or no liver or intestine.
Adults—liver with little or no bone or intestine; after age 50, increasing amounts of bone.
Vitamin B12 deficiency
Nutritional deficiency of zinc or magnesium
Excess vitamin D ingestion
Milk-alkali (Burnett) syndrome
Congenital hypophosphatasia (enzymopathy of liver, bone, kidney isoenzymes)
Pernicious anemia (one third of patients)
Postmenopausal women with osteoporosis taking estrogen replacement therapy
Therapeutic agents (e.g., corticosteroids, trifluoperazine, antilipemic agents, some hyperalimentation)
Cardiac surgery with cardiopulmonary bypass pump
Inherited metabolic diseases (Dubin-Johnson, Rotor, Gilbert, and Crigler-Najjar syndromes; type I–V glycogenoses, mucopolysaccharidoses; increased in Wilson disease and hemochromatosis related to hepatic fibrosis).
Consumption of alcohol by healthy persons (in contrast to GGT); may be normal even in alcoholic hepatitis.
In acute icteric viral hepatitis, the increase is less than two times normal in 90% of cases, but when ALP is high and serum bilirubin is normal, infectious mononucleosis should be ruled out as a cause of hepatitis.
The elevation in ALP tends to be more marked (more than threefold) in extrahepatic biliary obstruction (e.g., by stone or by cancer of the head of the pancreas) than in intrahepatic obstruction, and it is greater the more complete the obstruction. Serum enzyme activities may reach 10–12 times the upper limit of normal, returning to normal on surgical removal of the obstruction.
Day-to-day variation is 5–10%.
Recent food ingestion can increase as much as 30 U/L.
ALP is 15% and 10% higher in African American men and women, respectively, compared to other racial/ethnic groups.
Twenty-five percent higher with increased body mass index, 10% higher with smoking, 20% lower with the use of oral contraceptives.
Common drugs, including penicillin derivatives, antiepileptic drugs, antihistamines, cardiovascular drugs, etc., can increase blood levels.