What are the causes of elevated Alkaline Phosphatase (ALP) levels?

Causes of Elevated Alkaline Phosphatase (ALP)

Elevated ALP originates primarily from hepatobiliary disease or bone pathology, with cholestatic liver conditions, biliary obstruction, infiltrative diseases, and bone disorders representing the major etiologies. 1

Hepatobiliary Causes

Cholestatic Liver Diseases

• Primary biliary cholangitis, primary sclerosing cholangitis, and drug-induced cholestasis are major causes of chronic ALP elevation 1
• Cholestatic liver disease shows elevated ALP with or without elevated bilirubin, and isolated ALP elevation without other liver enzyme abnormalities strongly suggests cholestatic origin 2
• In patients with inflammatory bowel disease, elevated ALP should raise suspicion for primary sclerosing cholangitis 1

Biliary Obstruction

• Extrahepatic biliary obstruction from choledocholithiasis, malignant obstruction, biliary strictures, and infections causes chronic ALP elevation 1
• Approximately 18% of adults undergoing cholecystectomy have choledocholithiasis, which significantly impacts liver function tests 1
• Malignant biliary obstruction is a common cause of extremely high ALP levels (>1000 U/L) 3

Infiltrative Liver Diseases

• Hepatic metastases and amyloidosis are significant causes of ALP elevation 1
• In a 2024 observational study, 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 4
• Diffuse liver metastases can cause extremely high ALP elevations 3

Other Hepatic Conditions

• Cirrhosis, chronic hepatitis, viral hepatitis, and congestive heart failure are associated with ALP elevation 1
• Sepsis is a major cause of extremely high ALP levels (>1000 U/L), often with normal bilirubin 3
• In hospitalized patients with ALP >1000 U/L, the three major groups are obstructive biliary diseases, infiltrative liver disease, and sepsis 5

Drug-Induced Causes

• Older patients (≥60 years) are particularly prone to cholestatic drug-induced liver injury, comprising up to 61% of cases 1
• Medication review is crucial in the initial evaluation of isolated elevated ALP 1

Bone-Related Causes

Primary Bone Disorders

• Paget's disease, bony metastases, and fractures are significant sources of ALP elevation 1
• In postmenopausal women, elevated ALP is mainly caused by high bone turnover, which decreases with bisphosphonate treatment 6
• Bone metastases from malignancy are common, with 52 patients in one study having isolated bony metastasis causing elevated ALP 4

Bone Turnover States

• Elevated ALP in postmenopausal women correlates strongly with bone-specific alkaline phosphatase (BAP) and responds to bisphosphonate therapy 6
• ALP levels are physiologically higher in childhood due to bone growth 1

Physiologic Causes

• Pregnancy causes elevated ALP due to placental production 1
• Childhood growth results in physiologically elevated ALP levels 1

Severity Classification and Clinical Significance

The American College of Radiology classifies ALP elevation severity as: 2, 1

• Mild: <5 times the upper reference limit
• Moderate: 5-10 times the upper reference limit
• Severe: >10 times the upper reference limit

Severe elevation (>10× ULN) requires expedited workup given its high association with serious pathology 1

Diagnostic Approach to Determine Source

Confirming Hepatic vs. Bone Origin

• Measuring GGT concurrently with ALP confirms hepatobiliary origin when elevated; normal GGT suggests bone or other non-hepatic sources 1
• If GGT is unavailable or equivocal, ALP isoenzyme fractionation determines the percentage derived from liver versus bone 1
• Measuring 5'-nucleotidase can help, as elevations generally signal hepatobiliary disease 1

First-Line Imaging

• Abdominal ultrasound should be performed as first-line imaging for suspected hepatic origin to assess for dilated ducts, infiltrative lesions, or masses 1
• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP 1

Bone Evaluation

• Bone scan is indicated for patients with localized bone pain or elevated ALP suggesting bone origin 1
• Bone-specific alkaline phosphatase (B-ALP) measurement is useful for suspected bone origin, serving as a sensitive marker for bone turnover and bone metastases 1

Important Clinical Pitfalls

• In patients with sepsis, ALP can be extremely elevated with normal bilirubin, which may mislead clinicians away from considering infection 3
• Approximately 47% of patients with isolated elevated ALP of unclear etiology died within an average of 58 months, highlighting the potential clinical significance 4
• Bisphosphonates and denosumab can alter ALP levels despite underlying pathology, potentially masking disease activity 1
• In patients with common variable immunodeficiency (CVID), approximately 40% have abnormal liver function tests, with increased ALP being the most frequent abnormality 1