What causes elevated alkaline phosphatase (ALP) levels in the blood?

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) levels are most commonly caused by cholestatic liver diseases, bone disorders, or physiologic states, with the specific etiology determined by measuring GGT to differentiate hepatic from non-hepatic sources. 1

Primary Hepatobiliary Causes

Cholestatic Liver Diseases

• Primary biliary cholangitis, primary sclerosing cholangitis, drug-induced cholestasis, and partial bile duct obstruction are the major hepatic 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, hepatic metastases, and sarcoidosis cause isolated ALP elevation 1
• In a recent observational study, underlying malignancy accounted for 57% of isolated elevated ALP cases, with 61 patients having infiltrative intrahepatic malignancy 2
• Cirrhosis, chronic hepatitis, viral hepatitis, and congestive heart failure are associated with ALP elevation 1

Drug-Induced Causes

• Cholestatic drug-induced liver injury comprises up to 61% of cases in patients ≥60 years, making medication review crucial in older patients 1
• Anticonvulsants and glucocorticoids can induce ALP elevation 3
• Parenteral nutrition causes 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
• In the observational study, bone disease accounted for 29% of isolated elevated ALP cases, with 52 patients having bony metastasis 2
• In postmenopausal women, elevated ALP is mainly caused by high bone turnover, with ALP levels in people in their 80s significantly higher than those in their 60s 4

Malignancy-Related Bone Disease

• Bone metastases are a common cause, with 34 patients in one study having both hepatic and bone metastasis 2
• Patients under 40 years with suspected bone pathology and elevated ALP may require urgent referral to a bone sarcoma center 1

Physiologic Causes

• Childhood and pregnancy are physiologic causes of elevated ALP 1
• ALP levels are physiologically higher in childhood due to bone growth 1
• Pregnancy causes elevation due to placental production 1

Infectious and Inflammatory Causes

Sepsis

• Sepsis is one of the most frequent causes of extremely high ALP elevations (>1000 U/L), including gram-negative organisms, gram-positive organisms, and fungal sepsis 5
• Seven of 10 patients with sepsis had extremely high ALP with normal bilirubin 5
• In Thai hospitalized patients, sepsis was among the three major groups with high serum ALP levels 6

AIDS-Related Causes

• In AIDS patients, elevated ALP can result from sepsis, mycobacterium avium intracellulare (MAI) infection, cytomegalovirus infection, or drug toxicity 5

Special Clinical Contexts

Wilson Disease

• Markedly subnormal serum ALP (typically <40 IU/L) is characteristic of Wilson disease in acute liver failure presentations, occurring alongside Coombs-negative hemolytic anemia and coagulopathy 7
• A ratio of ALP to total bilirubin of <2 strongly suggests Wilson disease 7

Inflammatory Bowel Disease

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

Common Variable Immunodeficiency

• Approximately 40% of patients with CVID have abnormalities in liver function tests, with increased ALP the most frequent abnormality 1

Diagnostic Approach Algorithm

Step 1: Confirm Hepatic vs. Non-Hepatic Origin

• Measure GGT concurrently with ALP: elevated GGT confirms hepatobiliary origin, while normal GGT suggests bone or other non-hepatic sources 1
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone 1

Step 2: Severity Classification

• Mild elevation: <5× upper limit of normal (ULN)
• Moderate elevation: 5-10× ULN
• Severe elevation: >10× ULN (requires expedited workup due to high association with serious pathology) 1

Step 3: For Hepatic Origin

• Review medication history, particularly in patients ≥60 years 1
• Perform abdominal ultrasound as first-line imaging to assess for dilated ducts, gallstones, and masses 1
• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP 1
• Consider viral hepatitis serologies (HAV, HBV, HCV) if risk factors are present 1

Step 4: For Bone Origin

• Bone scan is indicated for localized bone pain or elevated ALP suggesting bone origin 1
• Bone-specific ALP (B-ALP) measurement can be useful for suspected bone origin, as it is a sensitive marker for bone turnover and bone metastases 1

Step 5: Monitor and Reassess

• If initial evaluation is unrevealing, repeat ALP measurement in 1-3 months 1
• Monitor closely if ALP continues to rise, as this may indicate progression of underlying disease 1

Important Clinical Pitfalls

• Do not attribute isolated ALP elevation ≥2× ULN to non-alcoholic steatohepatitis (NASH), as this is atypical in NASH 1
• Antiresorptive medications like bisphosphonates and denosumab can alter ALP levels despite underlying pathology 1, 4
• An isolated elevated ALP of unclear etiology is associated with metastatic intrahepatic malignancy in 57% of cases and carries significant mortality risk, with 47% of patients dying within an average of 58 months 2
• In patients with PSC, abrupt ALP elevations may reflect transient obstruction from inflammation, bacterial cholangitis, sludge, or choledocholithiasis rather than drug-induced liver injury 1