Evidence-based answer
There is no evidence regarding the differential diagnosis of an elevated AP level in a primary care asymptomatic population. The diagnoses and workup for elevated AP is based on case series of hospitalized patients. In these case series, 20% to 30% of the patients continue to have an unexplained elevation in AP after extensive workup, suggesting that the elevated AP level is a false positive. False-positive results can be expected to be even higher in an asymptomatic population. Various factors (height, weight, sex, smoking status, age, blood type, and hormonal status) contribute to an isolated benign elevation in AP.1-2 Age- and sex-dependent percentiles have been published.2 (Grade of recommendation: C, based on case series)
Recommendations from others
According to the Canadian Association of Gastroenterology Practice guidelines, an elevation in AP is associated with cholestatic liver disease, pregnancy, bone disease, and occasionally with inflammatory bowel disease. For an elevation in AP greater than 1.5 times the upper limits of normal (ULN) on 2 occasions at least 6 months apart, a workup for liver and bone disease is recommended followed by a referral to a specialist in hepatobiliary disease.3
Evidence summary
Liver, bone, and placental isoenzymes of AP are the most common sources of elevations reported in standard textbooks. Studies of men, women, and children have identified factors associated with normal elevations in AP. Hospital and laboratory-based studies report a variety of diseases associated with elevated AP. Within-day biologic variation is estimated at 4%, and day-to-day variation is estimated at 8% to 10%.2 The Table 1 shows the causes of normal or physiologic elevations and pathologic elevations.
In a case series of hospitalized Department of Veterans Affairs patients (95% men; average age=62), 87 charts were reviewed.4 Those patients had elevated AP with normal aspartate aminotransferase (serum glutamate oxaloacetate transaminase) and calcium values. Seventy-eight percent of the diagnoses could be made through a careful history, physical examination, routine laboratory tests (lactate dehydrogenase, bilirubin, phosphorus, creatinine, protein, and albumin), and admitting chest X-ray. In this cohort, 32% of elevated AP values resolved in 3 months, another 20% resolved in 12 months, and 20% persisted. In the remaining 28%, an explanation was not sought because of the presence of an obvious terminal illness or severe dementia. Persistence was associated with an AP value greater than 1.5 times the ULN. In 19 (22%), the AP elevation was unexplained. In a case series of patients referred for bone scan secondary to an elevated AP not due to hepatic causes, 21% had normal findings, and of these, 92% had AP values less than 3 times the ULN.5 In this group, patients were subsequently found to have uncontrolled diabetes mellitus, ethanol abuse, drug toxicity, renal abnormalities, and chronic active hepatitis.
Expert opinion as reflected in standard textbooks and opinion pieces suggests values of 1.5 to 3 times the ULN are consistent with hepatocellular (viral infection, drug toxicity, alcohol) etiology, while values greater than 3 times the ULN are usually associated with biliary involvement. Bone involvement can be found at any value. Extremely high values (>7 times the ULN) are associated with the familial and transient isolated hyperphosphatasemia of infancy. Further workup should evaluate the presence of liver or bone disease, familial patterns, and rarely preclinical cancers.
CLINICAL COMMENTARY
Les Hall, MD
University of Missouri–Columbia
Although alkaline phosphatase elevation does not always signal the presence of disease, any elevation would prompt me to review the patient’s use of medication, looking for hepatotoxic drugs. If substantial elevation persisted, I would check the gamma-glutamyltransferase (GGT) level, as increases in this enzyme indicate that the source of the alkaline phosphatase is from the liver. Key tests for evaluating possible liver disease would include an ultrasound of the liver and biliary system and an anti-mitochondrial antibody to look for primary biliary cirrhosis. If the GGT level was normal, I would search for abnormalities of bone as the cause of the elevated alkaline phosphatase.