What can cause elevated alkaline phosphatase (ALP) levels?

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) is most commonly caused by cholestatic liver diseases (primary biliary cholangitis, primary sclerosing cholangitis, biliary obstruction), bone disorders (Paget's disease, metastases, fractures), infiltrative liver diseases (malignancy, amyloidosis, sarcoidosis), and sepsis. 1

Hepatobiliary Causes

Cholestatic Liver Diseases

• Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most common chronic cholestatic conditions causing persistent ALP elevation 2
• PSC characteristically presents with episodes of cholangitis causing abrupt elevations of ALP, which may reflect transient obstruction from inflammation, bacterial cholangitis, sludge, or choledocholithiasis 2
• Drug-induced cholestasis is particularly common in older patients, comprising up to 61% of cases in patients ≥60 years 1

Biliary Obstruction

• Extrahepatic biliary obstruction from choledocholithiasis, malignant obstruction, and biliary strictures are major causes 2
• Approximately 18% of adults undergoing cholecystectomy have choledocholithiasis, which significantly impacts liver function tests 1, 2
• When gallstones migrate to the common bile duct, they cause partial or complete biliary obstruction leading to cholestasis and elevated ALP 1

Infiltrative Liver Diseases

• Infiltrative diseases, particularly hepatic metastases, are a leading cause of isolated elevated ALP 2
• In a recent observational study, underlying malignancy was the most common cause (57%) of isolated elevated ALP of unclear etiology, with 61 patients having infiltrative intrahepatic malignancy, 52 having bony metastasis, and 34 having both 3
• Non-malignant infiltrative diseases including amyloidosis and sarcoidosis also cause isolated ALP elevation 1, 2

Other Hepatic Conditions

• Cirrhosis, chronic hepatitis, viral hepatitis, and congestive heart failure are associated with ALP elevation 1
• ALP elevation ≥2× upper limit of normal is atypical in nonalcoholic steatohepatitis (NASH), making NASH an unlikely cause of significantly elevated ALP 1, 2

Sepsis-Related Cholestasis

• Sepsis is a major cause of extremely high ALP elevations (>1,000 U/L), including gram-negative organisms, gram-positive organisms, and fungal sepsis 4
• Notably, 7 of 10 patients with sepsis had extremely high ALP levels with normal bilirubin 4
• In Thai hospitalized patients, sepsis was one of three major groups with high serum ALP levels 5

Bone-Related Causes

• Bone disorders including Paget's disease, bony metastases, and fractures are significant sources of ALP elevation 1
• In the observational study, bone disease accounted for 29% of isolated elevated ALP cases 3
• Bone-specific alkaline phosphatase (B-ALP) is a sensitive marker for bone turnover and bone metastases 1

Physiologic Causes

• Childhood and pregnancy can lead to elevated ALP levels 1
• ALP levels are physiologically higher in childhood due to bone growth 1
• Pregnancy causes elevation due to placental production 1

Special Populations and Conditions

Inflammatory Bowel Disease

• In patients with inflammatory bowel disease, elevated ALP should raise suspicion of primary sclerosing cholangitis 1, 2

AIDS/HIV

• Nine patients with AIDS had elevated ALP in one study, with causes including sepsis, mycobacterium avium intracellulare (MAI) infection, cytomegalovirus infection, and drug toxicity 4

Common Variable Immunodeficiency

• Approximately 40% of patients with common variable immunodeficiency (CVID) have abnormalities in liver function tests, with increased ALP the most frequent abnormality 1

Rare Genetic Conditions

• Benign familial hyperphosphatasemia can cause markedly elevated intestinal alkaline phosphatase levels (29% to 44% of total) in all family members 6

Severity Classification

The severity of ALP elevation guides diagnostic urgency and differential diagnosis 1, 2:

• Mild elevation: <5× upper limit of normal (ULN)
• Moderate elevation: 5-10× ULN
• Severe elevation: >10× ULN (requires expedited workup due to high association with serious pathology)

Critical Diagnostic Considerations

Confirming Hepatobiliary Origin

• Measure GGT concurrently with ALP to confirm hepatobiliary origin; elevated GGT confirms liver source while normal GGT suggests bone or other non-hepatic sources 1, 2
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage from liver versus bone 1, 2

Important Clinical Pitfalls

• Extremely high elevations of ALP (>1,000 U/L) are most frequently seen in patients with sepsis, malignant obstruction, and AIDS 4
• Patients with sepsis can have extremely high ALP levels with normal bilirubin, which may mislead clinicians 4
• An isolated elevated ALP of unclear etiology is uncommonly associated with primary parenchymal liver disease 3
• In the observational study, 47% of patients with isolated elevated ALP died within an average of 58 months, highlighting the potential clinical significance 3
• Treatments like bisphosphonates and denosumab can alter ALP levels despite underlying pathology 1

Parenteral Nutrition

• Parenteral nutrition can cause ALP elevation through chronic cholestasis, with a reported incidence of up to 65% in home parenteral nutrition patients, particularly with excessive intravenous lipid administration (>1g/kg/day) 1