What causes elevated alkaline phosphatase (alk phos) levels?

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) most commonly originates from hepatobiliary disease (cholestatic liver disorders, biliary obstruction, infiltrative liver disease) or bone disease (Paget's disease, metastases, fractures), with the first step being to confirm the source by measuring gamma-glutamyl transferase (GGT). 1

Primary Hepatobiliary Causes

Cholestatic liver diseases are the predominant hepatic causes of chronic ALP elevation: 1

• Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) represent the major cholestatic disorders, with PSC showing ALP elevation in approximately 75% of patients and strong association with inflammatory bowel disease 1, 2
• Drug-induced cholestasis is particularly important in older patients, comprising up to 61% of cholestatic liver injury cases in patients ≥60 years 1
• Biliary obstruction from choledocholithiasis, malignant obstruction, biliary strictures, or infections causes extrahepatic cholestasis 1

Infiltrative liver diseases include: 1

• Hepatic metastases (57% of unexplained isolated ALP elevations are due to malignancy, with 47% mortality within 58 months) 3
• Amyloidosis and sarcoidosis 1
• Cirrhosis and chronic hepatitis 1

Sepsis is a critical cause, particularly with extremely high ALP levels (>1000 U/L), where 70% of septic patients can have markedly elevated ALP with normal bilirubin 4, 5

Bone-Related Causes

Primary bone disorders causing ALP elevation include: 1

• Paget's disease of bone 1
• Bony metastases (52 patients in one cohort had isolated bone metastases causing elevated ALP) 3
• Fractures and increased bone turnover 1

Physiologic and Benign Causes

Normal physiologic states that elevate ALP: 1

• Childhood and adolescence (ALP levels are 2-3× adult values due to bone growth) 1
• Pregnancy (placental production) 1
• Benign familial hyperphosphatasemia (intestinal ALP variant, a rare but important benign condition to recognize to avoid unnecessary workup) 6, 7

Diagnostic Algorithm

Step 1: Confirm hepatic origin 1, 2

• 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 percentage from liver versus bone 1

Step 2: Severity classification guides urgency 1

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

Step 3: For confirmed hepatobiliary origin 1

• Review medication history thoroughly (especially in patients ≥60 years) 1
• Obtain abdominal ultrasound as first-line imaging to assess for dilated ducts, gallstones, infiltrative lesions, or masses 1
• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP, which is superior for detecting intrahepatic biliary abnormalities, PSC, and small duct disease 1

Step 4: For suspected bone origin 1

• Measure bone-specific ALP (B-ALP) if available 1
• Order bone scan only if patient has localized bone pain or clinical symptoms suggesting metastases 1
• In postmenopausal women without symptoms, bone metastases are less likely with mild ALP elevation 1

Critical Clinical Pitfalls

Do not assume NASH when ALP is ≥2× ULN, as significant ALP elevation is atypical for non-alcoholic steatohepatitis 1, 8

Do not overlook sepsis as a cause of extremely high ALP (>1000 U/L), particularly when bilirubin is normal—this pattern is seen in 70% of septic patients with markedly elevated ALP 4

Do not delay workup in patients with isolated elevated ALP of unclear etiology, as 57% have underlying malignancy with 47% mortality within 58 months of identification 3

Consider cholangiocarcinoma in endemic areas or high-risk populations presenting with obstructive biliary disease patterns 5

Recognize that treatments like bisphosphonates and denosumab can alter ALP levels despite underlying bone pathology 1

Special Population Considerations

In inflammatory bowel disease patients with elevated ALP, obtain high-quality MRCP to evaluate for PSC, and if MRCP is normal but suspicion remains high, consider liver biopsy for small-duct PSC 1

In patients with common variable immunodeficiency (CVID), approximately 40% have abnormal liver function tests with increased ALP being the most frequent abnormality 1

In chronic kidney disease patients on dialysis, elevated ALP predicts fracture risk and should prompt bone turnover assessment 1