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

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) most commonly results from hepatobiliary disease (cholestatic disorders, biliary obstruction, infiltrative liver disease), bone disorders (Paget's disease, metastases, fractures), or physiologic states (childhood growth, pregnancy), with the specific cause determined by clinical context and confirmatory testing with GGT or bone-specific ALP. 1

Hepatobiliary Causes

Cholestatic Liver Diseases

• Primary biliary cholangitis, primary sclerosing cholangitis, and drug-induced cholestasis are major causes of chronic ALP elevation 1
• In patients with inflammatory bowel disease, elevated ALP should raise suspicion for primary sclerosing cholangitis 1
• Drug-induced cholestatic liver injury comprises up to 61% of cases in patients ≥60 years, making medication review crucial 1

Biliary Obstruction

• Extrahepatic biliary obstruction from choledocholithiasis, malignant obstruction, biliary strictures, and infections causes ALP elevation 1
• Approximately 18% of adults undergoing cholecystectomy have choledocholithiasis, which significantly impacts liver function tests 1
• Malignant biliary obstruction is a frequent cause of extremely high ALP levels (>1000 U/L) in hospitalized patients 2, 3

Infiltrative Liver Disease

• Hepatic metastases and amyloidosis cause chronic ALP elevation 1
• In one study of isolated elevated ALP, 57% were due to underlying malignancy, with 61 patients having infiltrative intrahepatic malignancy 4
• Diffuse liver metastases can cause extremely high ALP elevations 2

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, often with normal bilirubin 2, 3
• 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

Bone-Related Causes

Primary Bone Disorders

• Paget's disease, bony metastases, and fractures are significant sources of ALP elevation 1
• Bone disease accounted for 29% of cases in one study of isolated elevated ALP 4
• Localized bone pain with elevated ALP warrants bone scan evaluation 1

Physiologic Causes

• ALP levels are physiologically higher in childhood due to bone growth 1
• Pregnancy causes elevated ALP due to placental production 1

Diagnostic Approach Algorithm

Step 1: Confirm Hepatic vs. Bone Origin

• Measure GGT: elevated GGT confirms hepatic origin; normal GGT suggests bone origin 1
• Alternatively, bone-specific alkaline phosphatase (B-ALP) can be measured for suspected bone origin 1

Step 2: For Hepatic Origin

• Review medication history thoroughly, especially in older patients who are more prone to cholestatic drug-induced liver injury 1
• Assess for symptoms: right upper quadrant pain, fatigue, nausea, weight loss 1
• Perform abdominal ultrasound as first-line imaging to assess for dilated ducts and gallstones 5, 1
• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP 1
• If common bile duct stones are demonstrated on ultrasound, proceed directly to ERCP 1

Step 3: Severity Classification Guides Urgency

• Mild elevation: <5 times upper limit of normal (ULN) 1
• Moderate elevation: 5-10 times ULN 1
• Severe elevation: >10 times ULN 1

Step 4: Special Considerations

• In patients with conjugated hyperbilirubinemia, assess for concomitant alkaline phosphatase elevations and exclude biliary obstruction 5
• If initial evaluation is unrevealing, repeat ALP measurement in 1-3 months and monitor closely if ALP continues to rise 1
• Approximately 40% of patients with common variable immunodeficiency have abnormalities in liver function tests, with increased ALP the most frequent abnormality 1

Critical Clinical Pitfalls

• Do not attribute isolated ALP elevation ≥2× ULN to non-alcoholic steatohepatitis (NASH), as this is atypical 1
• Absence of gallstones on imaging with elevated ALP suggests non-gallstone etiology, while normal caliber extrahepatic bile duct suggests intrahepatic cholestasis 1
• Treatments like bisphosphonates and denosumab can alter ALP levels despite underlying pathology 1
• In patients with suspected malignancy presenting with isolated elevated ALP, 47% died within an average of 58 months, highlighting the clinical significance 4
• Alcohol-induced hepatitis can transiently increase serum ALP levels even in patients with underlying hypophosphatasia, potentially masking the diagnosis 6