What Can Increase Alkaline Phosphatase Enzyme Levels
Alkaline phosphatase (ALP) elevation occurs through two primary mechanisms: increased production from hepatobiliary disease, bone disorders, or physiologic states, and increased release from tissue injury or obstruction. 1
Hepatobiliary Causes
Cholestatic liver diseases are the most common pathologic hepatic causes of chronic ALP elevation, including: 1
- Primary biliary cholangitis and primary sclerosing cholangitis - major cholestatic conditions causing sustained ALP elevation 1
- Biliary obstruction - both intrahepatic and extrahepatic sources including choledocholithiasis (present in approximately 18% of adults undergoing cholecystectomy), malignant obstruction, biliary strictures, and infections 1
- Drug-induced cholestasis - particularly important in older patients, where cholestatic drug-induced liver injury comprises up to 61% of cases in patients ≥60 years 1
- Infiltrative liver diseases - including amyloidosis, hepatic metastases, and sarcoidosis 1
- Chronic liver conditions - cirrhosis, chronic hepatitis, viral hepatitis, and congestive heart failure 1
- Parenteral nutrition - can cause ALP elevation through chronic cholestasis with reported incidence up to 65% in home parenteral nutrition patients, especially with excessive intravenous lipid administration (>1g/kg/day) 1
Bone-Related Causes
Bone disorders represent the second major category of ALP elevation, particularly when GGT is normal: 1
- Paget's disease of bone - a significant source of marked ALP elevation 1
- Bone metastases - associated with increased osteoblastic activity and elevated ALP, particularly in prostate cancer 1
- Fractures - acute bone injury causes ALP release 1
- X-linked hypophosphatemia (XLH) - presents with elevated ALP as a biochemical hallmark, along with hypophosphatemia and elevated FGF23 1
- Osteomalacia and rickets - serum ALP is a reliable biomarker of rickets activity and osteomalacia in children and adults 1
Physiologic Causes
Certain physiologic states cause benign ALP elevation that requires no intervention: 1
- Childhood and adolescence - ALP levels are physiologically 2-3× adult values due to bone growth 1
- Pregnancy - elevated due to placental production of ALP 1
- High fat diets - can cause transient elevation 2
Medication-Induced Elevation
Several medications directly induce ALP production: 1, 2
- Glucocorticoids - induce ALP enzyme production 2
- Anticonvulsants - can cause drug-induced cholestasis and ALP elevation 2
Malignancy-Related Causes
Neoplastic processes elevate ALP through multiple mechanisms: 1, 3
- Cholangiocarcinoma - causes marked elevation of serum ALP through biliary obstruction 3
- Hepatic metastases - infiltrative disease elevates ALP 1
- Bone metastases - particularly from prostate, breast, and lung cancers 1
Other Pathologic Causes
Additional conditions that can elevate ALP include: 1, 3
- Sepsis - commonly associated with high serum ALP levels in hospitalized patients 3
- Endocrine diseases - various hormonal disorders can affect ALP levels 2
- Common variable immunodeficiency (CVID) - approximately 40% of patients have abnormalities in liver function tests, with increased ALP the most frequent abnormality 1
- Benign familial hyperphosphatasemia - a hereditary condition causing persistently elevated intestinal and liver/bone/kidney ALP isoenzymes without underlying disease 4
Important Clinical Considerations
The magnitude of ALP elevation provides diagnostic clues: 1
- Mild elevation (<5× ULN) - may represent physiologic causes, early cholestatic disease, or bone disorders 1
- Moderate elevation (5-10× ULN) - typically indicates significant hepatobiliary disease or active bone pathology 1
- Severe elevation (>10× ULN) - requires expedited workup given high association with serious pathology such as biliary obstruction, infiltrative disease, or malignancy 1
Measuring GGT concurrently helps determine the source: elevated GGT confirms hepatic origin, while normal GGT suggests bone or other non-hepatic sources 1