What causes elevated alkaline phosphatase (ALP) levels?

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) is most commonly caused by cholestatic liver disease, bone disorders, or malignancy, requiring systematic evaluation starting with gamma-glutamyl transferase (GGT) measurement to determine hepatic versus non-hepatic origin. 1

Primary Sources of ALP Elevation

ALP originates from multiple tissues, with the liver (canalicular membrane of hepatocytes and biliary epithelium) and bone being the predominant sources. 2 Other tissues including intestines, kidneys, white blood cells, and placenta produce smaller amounts. 2

Hepatobiliary Causes

When GGT is concomitantly elevated, confirming hepatic origin, the differential includes: 1, 2

Cholestatic Liver Diseases

• Primary biliary cholangitis and primary sclerosing cholangitis are major causes of chronic ALP elevation 1
• Drug-induced cholestasis, particularly in patients ≥60 years where it comprises up to 61% of cholestatic cases 1
• Partial bile duct obstruction 1

Extrahepatic Biliary Obstruction

• Choledocholithiasis (present in approximately 18% of adults undergoing cholecystectomy) 1
• Malignant obstruction (one of the most common causes of extremely high ALP >1000 IU/L) 3, 4
• Biliary strictures 1

Infiltrative Liver Diseases

• Hepatic metastases (in one study, 57% of isolated elevated ALP cases were due to malignancy, with 61 patients having infiltrative intrahepatic disease) 5
• Amyloidosis and sarcoidosis 1

Other Hepatic Conditions

• Cirrhosis, chronic hepatitis, and viral hepatitis 1
• Congestive heart failure 1
• Sepsis (a major cause of extremely high ALP, often with normal bilirubin in 70% of septic patients) 3

Bone-Related Causes

When GGT is normal with elevated ALP, suggesting bone origin: 1, 2

• Paget's disease of bone 1
• Bony metastases (52 patients in one cohort had isolated bone metastasis causing elevated ALP) 5
• Fractures and high bone turnover 1
• Postmenopausal bone turnover (may normalize with bisphosphonate therapy) 2

Physiologic Causes

• Childhood and adolescence due to active bone growth 1
• Pregnancy due to placental production 1

Severity Classification and Clinical Implications

The American College of Radiology classifies ALP elevation as: 6, 1

• Mild: <5 times upper limit of normal (ULN)
• Moderate: 5-10 times ULN
• Severe: >10 times ULN (requires expedited workup)

Extremely high ALP levels (>1000 IU/L) are most commonly associated with sepsis, malignant biliary obstruction, and AIDS. 3, 4 In one study, the three major groups with markedly elevated ALP were obstructive biliary diseases, infiltrative liver disease, and sepsis. 4

Diagnostic Algorithm

Step 1: Confirm Hepatic vs. Non-Hepatic Origin

• Measure GGT concurrently: Elevated GGT confirms hepatobiliary origin; normal GGT suggests bone or other non-hepatic sources 1, 2
• Alternative: Measure 5'-nucleotidase (elevations signal hepatobiliary disease) or ALP isoenzyme fractionation 1, 2

Step 2: If Hepatic Origin Confirmed

• Obtain abdominal ultrasound as first-line imaging to assess for dilated ducts, gallstones, or masses 1
• If ultrasound negative but ALP remains elevated: Proceed to MRI with MRCP 1
• Review medication history (particularly in older patients for drug-induced cholestasis) 1
• Check viral hepatitis serologies if risk factors present 1

Step 3: If Bone Origin Suspected

• Bone scan indicated for localized bone pain or clinical symptoms 1
• Consider bone-specific ALP (B-ALP) measurement as a sensitive marker for bone turnover and metastases 1
• Patients under 40 with suspected bone pathology may require urgent referral to bone sarcoma center 1

Critical Pitfalls to Avoid

• Do not assume all ALP elevations are liver-related without confirming source with GGT 2
• In sepsis, ALP can be extremely elevated with normal bilirubin, which may mislead clinicians away from the diagnosis 3
• Isolated elevated ALP of unclear etiology carries significant mortality risk: 47% of patients in one cohort died within average 58 months, predominantly from underlying malignancy 5
• In inflammatory bowel disease patients with elevated ALP, maintain high suspicion for primary sclerosing cholangitis and obtain high-quality MRC 1
• Cholangiocarcinoma is an important consideration in endemic areas with markedly elevated ALP 4

Special Clinical Contexts

• Benign familial hyperphosphatasemia exists as a rare hereditary condition with markedly elevated intestinal ALP isoenzyme (29-44% of total), requiring recognition to avoid unnecessary workup 7
• Common variable immunodeficiency (CVID): Approximately 40% have abnormal liver function tests, with increased ALP being the most frequent abnormality 1
• X-linked hypophosphatemia presents with elevated ALP alongside hypophosphatemia and elevated FGF23 1