What are the causes of elevated alkaline phosphatase (ALP) levels?

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) originates primarily from hepatobiliary disease or bone pathology, with malignancy (particularly metastatic disease) being the most common cause in adults presenting with isolated, unexplained elevation. 1, 2

Primary Hepatobiliary Causes

Cholestatic Liver Diseases

• Primary biliary cholangitis, primary sclerosing cholangitis, drug-induced cholestasis, and partial bile duct obstruction are major causes of chronic ALP elevation 1
• Extrahepatic biliary obstruction from choledocholithiasis, malignant obstruction, biliary strictures, and infections commonly elevate ALP 1
• Approximately 18% of adults undergoing cholecystectomy have choledocholithiasis, which significantly impacts liver function tests 1

Infiltrative and Parenchymal Liver Disease

• Infiltrative diseases including amyloidosis, sarcoidosis, and hepatic metastases cause chronic ALP elevation 1
• Cirrhosis, chronic hepatitis, viral hepatitis, and congestive heart failure are associated with ALP elevation 1
• Parenteral nutrition can cause ALP elevation through chronic cholestasis, with incidence up to 65% in home parenteral nutrition patients, particularly with excessive intravenous lipid administration (>1g/kg/day) 1

Severe/Extreme Elevations (>1000 U/L)

• Sepsis is the most frequent cause of extremely high ALP levels, including gram-negative, gram-positive, and fungal organisms 3
• Notably, patients with sepsis can have extremely high ALP with normal bilirubin (7 of 10 patients in one series) 3
• Malignant biliary obstruction and AIDS-related infections (including MAI and CMV) are other common causes of extreme elevation 3

Primary Bone Causes

Malignant Bone Disease

• Metastatic bone disease is a leading cause, with 57% of patients with isolated elevated ALP having underlying malignancy (52 patients with bony metastasis alone, 34 with both hepatic and bone metastasis) 2
• Bone-specific ALP is a sensitive marker for bone turnover and bone metastases 1

Benign Bone Disease

• Paget's disease of bone causes significant ALP elevation 1, 3
• Fractures and other bone disorders contribute to elevated ALP 1
• Bone disease accounted for 29% of patients with isolated elevated ALP in one large cohort 2

Physiologic Causes

• Childhood growth causes physiologically elevated ALP due to active bone growth 1
• Pregnancy elevates ALP due to placental production 1

Special Clinical Contexts

Metabolic Bone Disease

• X-linked hypophosphatemia (XLH) presents with elevated ALP as a biochemical hallmark, along with hypophosphatemia and elevated FGF23 4
• Serum ALP is a reliable biomarker of rickets activity and osteomalacia in children and adults 4

Immunodeficiency

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

Inflammatory Bowel Disease

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

Diagnostic Approach Algorithm

Step 1: Confirm Hepatic vs. Bone Origin

• Measure GGT concurrently with ALP to confirm hepatobiliary origin; normal GGT suggests bone or other non-hepatic sources 1
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine percentage from liver versus bone 1
• Bone-specific ALP measurement is useful for suspected bone origin 1

Step 2: Severity Classification Guides Urgency

• Mild elevation (<5× ULN): Standard workup 1
• Moderate elevation (5-10× ULN): Expedited evaluation 1
• Severe elevation (>10× ULN): Requires urgent workup given high association with serious pathology 1

Step 3: Hepatobiliary Workup (if GGT elevated)

• Abdominal ultrasound as first-line imaging to assess for dilated ducts, gallstones, and masses 1
• If ultrasound negative but ALP remains elevated, proceed to MRI with MRCP 1
• Review medication history, particularly in older patients (cholestatic drug-induced liver injury comprises up to 61% of cases in patients ≥60 years) 1
• Consider viral hepatitis serologies (HAV, HBV, HCV) if risk factors present 1

Step 4: Bone Workup (if GGT normal)

• Bone scan indicated for localized bone pain or clinical symptoms suggesting bone pathology 1
• Patients under 40 with suspected bone pathology may require urgent referral to a bone sarcoma center 1

Step 5: Consider Malignancy

• Isolated elevated ALP of unclear etiology is most commonly due to metastatic intrahepatic malignancy (61 patients with infiltrative intrahepatic malignancy in one cohort) 2
• 47% of patients with isolated elevated ALP died within average of 58 months, underscoring clinical significance 2

Critical Pitfalls to Avoid

• Do not dismiss isolated ALP elevation as benign—it carries significant mortality risk, with malignancy being the most common cause 2
• Sepsis can present with extremely high ALP and normal bilirubin, which may mislead clinicians away from infectious etiology 3
• In patients with IBD and elevated ALP, failure to evaluate for primary sclerosing cholangitis with high-quality MRC can miss this important diagnosis 1
• Antiresorptive medications (bisphosphonates, denosumab) can lower ALP levels, potentially masking underlying bone pathology 1
• If initial evaluation is unrevealing, repeat ALP in 1-3 months and monitor closely if it continues to rise 1