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

Most Common Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) is most commonly caused by cholestatic liver diseases (including biliary obstruction and primary biliary/sclerosing cholangitis), bone disorders (particularly Paget's disease and metastases), and malignancy (especially infiltrative liver disease and bony metastases). 1, 2

Primary Hepatic Causes

The hepatobiliary system is the predominant source of pathologic ALP elevation in adults:

Cholestatic and Obstructive Conditions

• Extrahepatic biliary obstruction from choledocholithiasis, malignant obstruction, biliary strictures, and infections represents a major cause of chronic ALP elevation 1
• Primary biliary cholangitis and primary sclerosing cholangitis are key cholestatic liver diseases causing sustained ALP elevation 1
• Approximately 18% of adults undergoing cholecystectomy have choledocholithiasis, which significantly impacts liver function tests 1
• Drug-induced cholestasis should be considered, particularly in older patients who comprise up to 61% of cholestatic drug-induced liver injury cases 1

Infiltrative and Parenchymal Liver Disease

• Infiltrative liver diseases, including amyloidosis and hepatic metastases, cause chronic ALP elevation 1
• Cirrhosis, chronic hepatitis, viral hepatitis, and congestive heart failure are associated with ALP elevation 1
• In one cohort of isolated elevated ALP, 61 patients had infiltrative intrahepatic malignancy as the underlying cause 3

Sepsis-Related Elevation

• Sepsis is a frequently overlooked cause of extremely high ALP levels (>1000 IU/L), with 10 of 31 patients in one series having sepsis as the primary etiology 4
• Notably, 7 of 10 patients with sepsis had extremely high ALP with normal bilirubin, making this diagnosis easily missed 4
• Gram-negative organisms, gram-positive organisms, and fungal infections can all cause marked ALP elevation 4

Primary Bone Causes

Bone disorders represent the second major category of ALP elevation:

• Paget's disease, bony metastases, and fractures are significant sources of ALP elevation 1
• In a cohort of isolated elevated ALP, 52 patients had bony metastasis alone, and 34 had both hepatic and bone metastasis 3
• High bone turnover in postmenopausal women can cause elevation that may normalize with bisphosphonate therapy 2
• Bone disease accounted for 29% of cases in one series of isolated elevated ALP 3

Malignancy as a Unifying Cause

Malignancy is the single most common cause when evaluating isolated elevated ALP of unclear etiology:

• In a 2024 observational study, 57% of patients (147 of 260) with isolated elevated ALP had underlying malignancy as the cause 3
• This included 61 patients with infiltrative intrahepatic malignancy, 52 with bony metastasis, and 34 with both 3
• Malignant biliary obstruction is among the most common causes of extremely high ALP levels 4, 5
• Notably, 47% of patients with isolated elevated ALP died within an average of 58 months, underscoring the clinical significance 3

Physiologic and Benign Causes

Not all ALP elevations indicate pathology:

• Childhood and pregnancy represent physiologic causes, with ALP levels higher during bone growth and due to placental production 1
• Benign familial hyperphosphatasemia exists as a hereditary condition with markedly elevated intestinal ALP isoenzyme 6
• High-fat diets can cause nonhepatic increases in ALP activity 7

Diagnostic Algorithm for Source Determination

The first step is determining whether the ALP originates from liver or bone:

Initial Laboratory Assessment

• Measure gamma-glutamyl transferase (GGT) to differentiate hepatic from non-hepatic origin 1, 2
• Concomitantly elevated GGT confirms liver as the likely source, while normal GGT with elevated ALP suggests bone origin 2
• Alternative tests include 5'-nucleotidase (elevated in hepatobiliary disease) or ALP isoenzyme fractionation 2

For Suspected Hepatic Origin

• Perform abdominal ultrasound as first-line imaging to assess for dilated ducts and gallstones 1, 2
• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP 1, 2
• Review medication history carefully, as drugs are a common cause, especially in patients ≥60 years 1
• In inflammatory bowel disease patients, elevated ALP should raise suspicion for primary sclerosing cholangitis, requiring high-quality MRC 1

For Suspected Bone Origin

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

Critical Pitfalls to Avoid

Do not assume all ALP elevations are liver-related without confirming the source with GGT or other testing 2

• Sepsis with normal bilirubin can present with extremely high ALP and be easily overlooked 4
• Malignancy must be actively excluded in isolated elevated ALP, as it represents the majority of cases and carries significant mortality 3
• Do not attribute isolated ALP elevation ≥2× ULN to non-alcoholic steatohepatitis (NASH), as this is atypical for NASH 1
• Remember that bisphosphonates and denosumab can alter ALP levels despite underlying pathology 1
• In acute liver failure with markedly subnormal ALP (<40 IU/L), consider Wilson disease, especially with Coombs-negative hemolytic anemia 8

Special Populations

Immunodeficiency Patients

• Approximately 40% of patients with common variable immunodeficiency (CVID) have abnormalities in liver function tests, with increased ALP the most frequent abnormality 9

Patients on Parenteral Nutrition

• 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