What causes an increase in alkaline phosphatase (ALP) levels?

Causes of Elevated Alkaline Phosphatase

Alkaline phosphatase elevation occurs primarily from hepatobiliary disease (cholestasis, obstruction, infiltration), bone disorders (Paget's disease, metastases, fractures), or physiologic states (pregnancy, childhood growth), with the specific cause determined by measuring GGT to differentiate hepatic from non-hepatic sources. 1

Primary Hepatobiliary Causes

Cholestatic liver diseases are the most common 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, from choledocholithiasis (present in ~18% of cholecystectomy patients), malignant obstruction, biliary strictures, or infections 1
• Drug-induced cholestasis - particularly important in older patients, where cholestatic drug injury comprises up to 61% of cases in patients ≥60 years 1
• Infiltrative liver diseases - including hepatic metastases, amyloidosis, and sarcoidosis 1

In patients with extremely high ALP levels (>1000 U/L), sepsis is a leading cause, accounting for approximately one-third of cases, and can present with markedly elevated ALP despite normal bilirubin levels. 2 Gram-negative, gram-positive, and fungal sepsis can all cause this pattern. 2

Malignancy as a Critical Cause

Malignancy is the most common cause of isolated, unexplained ALP elevation, accounting for 57% of cases in one cohort, with: 3

• Infiltrative intrahepatic malignancy (23% of cases) 3
• Bony metastases (20% of cases) 3
• Combined hepatic and bone metastasis (13% of cases) 3

This finding carries significant prognostic implications, as 47% of patients with isolated elevated ALP of unclear etiology died within an average of 58 months after identification. 3 An ALP level >160 U/L increases sensitivity for detecting liver metastases 12-fold compared to using the upper normal limit. 4

Bone-Related Causes

Non-malignant bone disorders account for approximately 29% of isolated ALP elevations: 3

• Paget's disease of bone - a classic cause of markedly elevated ALP 1
• Fractures - particularly healing fractures with active bone remodeling 1
• Osteomalacia - characterized by hypocalcemia, hypophosphataemia, elevated PTH, and elevated bone-specific ALP, though serum calcium and phosphate are often normal 1
• X-linked hypophosphatemia - presents with elevated ALP alongside hypophosphatemia and elevated FGF23 1

Physiologic Causes

Normal physiologic states can cause ALP elevation without pathology: 1

• Childhood and adolescence - ALP levels are physiologically higher due to active bone growth 1
• Pregnancy - placental production causes elevated ALP levels 1

Special Clinical Contexts

In patients with inflammatory bowel disease, elevated ALP should raise immediate suspicion for primary sclerosing cholangitis, requiring high-quality MRCP for diagnosis. 1 If MRCP is normal but suspicion remains high, liver biopsy should be considered to diagnose small-duct PSC. 1

In AIDS patients, multiple causes can coexist, including sepsis, mycobacterium avium intracellulare infection, cytomegalovirus infection, and drug toxicity. 2

Common variable immunodeficiency (CVID) is associated with liver function test abnormalities in ~40% of patients, with increased ALP being the most frequent abnormality. 1

Diagnostic Algorithm

The initial step is measuring GGT concurrently with ALP: 1

• Elevated GGT confirms hepatobiliary origin → proceed with abdominal ultrasound as first-line imaging 1
• Normal GGT suggests bone or other non-hepatic sources → consider bone-specific ALP measurement or bone scan if localized symptoms present 1

For hepatobiliary causes with negative ultrasound, proceed to MRI with MRCP, which is superior for detecting intrahepatic biliary abnormalities, PSC, and small duct disease. 1

Severity Classification and Urgency

ALP elevation severity guides workup urgency: 1

• Mild elevation (<5× ULN) - standard workup timeline
• Moderate elevation (5-10× ULN) - expedited workup warranted
• Severe elevation (>10× ULN) - requires urgent evaluation due to high association with serious pathology

Critical Pitfalls to Avoid

Do not attribute isolated ALP elevation ≥2× ULN to NASH, as this is atypical; NASH typically causes ALT elevation more than ALP. 1

In patients with PSC on treatment, abrupt ALP elevations may reflect transient obstruction from inflammation, bacterial cholangitis, sludge, or choledocholithiasis rather than drug-induced injury, requiring evaluation for dominant stricture with MRCP or ERCP. 1

Antiresorptive medications (bisphosphonates, denosumab) can alter ALP levels despite underlying pathology and should be reviewed in medication history. 1, 5