What are the possible causes of an elevated alkaline phosphatase (ALP) level?

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase results from hepatobiliary disease (cholestasis, obstruction, infiltration), bone disorders (Paget's disease, metastases, fractures), or physiologic states (childhood growth, pregnancy), with the most critical step being confirmation of hepatic versus bone origin by measuring GGT or ALP isoenzymes. 1

Primary Hepatic Causes

Cholestatic Liver Diseases

• Primary biliary cholangitis and primary sclerosing cholangitis are major causes of chronic ALP elevation, with PBC diagnosed when elevated ALP occurs alongside positive antimitochondrial antibody 1
• Drug-induced cholestasis is particularly common in patients ≥60 years, accounting for up to 61% of cholestatic liver injury cases in this age group 1
• Biliary obstruction from choledocholithiasis, malignant strictures, or infections produces marked ALP elevation, often with dilated bile ducts visible on imaging 1

Infiltrative Liver Diseases

• Hepatic metastases are the single most common cause of unexplained isolated ALP elevation in hospitalized adults, accounting for 57% of cases in one large cohort, with 61 patients having intrahepatic infiltration, 52 having bone metastases, and 34 having both 2
• Amyloidosis and sarcoidosis can cause isolated ALP elevation through hepatic infiltration 1
• Sepsis produces extremely high ALP levels (>1000 U/L) even with normal bilirubin in 70% of cases, caused by gram-negative organisms, gram-positive organisms, or fungal infections 3

Other Hepatic Conditions

• Cirrhosis, chronic hepatitis, and viral hepatitis are associated with ALP elevation, though typically less pronounced than in cholestatic diseases 1
• Congestive heart failure can elevate ALP through hepatic congestion 1

Bone-Related Causes

• Paget's disease of bone produces marked ALP elevation from increased osteoblastic activity 1
• Bone metastases elevate ALP through osteoblastic response, with 29% of unexplained isolated ALP elevations in one study attributed to bone disease 2
• Fractures cause transient ALP elevation during healing 1
• Renal osteodystrophy in chronic kidney disease patients causes isolated ALP elevation through secondary hyperparathyroidism and high-turnover bone disease, with bone disease present in nearly all dialysis patients 1

Physiologic Causes

• Childhood and adolescence produce ALP levels 2-3× adult values due to active bone growth 1
• Pregnancy elevates ALP in the second and third trimesters from placental production, with concurrent albumin reduction from hemodilution 1

Severity-Based Risk Stratification

ALP Elevation	Definition	Clinical Significance
Mild	<5× ULN	Routine workup appropriate [1]
Moderate	5-10× ULN	Expedited evaluation warranted [1]
Severe	>10× ULN	Urgent workup required due to high association with sepsis, malignant obstruction, or complete biliary blockage [1]

Diagnostic Algorithm

Step 1: Confirm 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, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone 1

Step 2: Initial Hepatobiliary Workup

• Perform abdominal ultrasound as first-line imaging to assess for dilated ducts, gallstones, infiltrative lesions, or masses 1
• Obtain complete liver panel including ALT, AST, total and direct bilirubin, and albumin 1
• Calculate the R value [(ALT/ULN)/(ALP/ULN)] to classify injury pattern: cholestatic (R ≤2), mixed (R >2 and <5), or hepatocellular (R ≥5) 1

Step 3: Advanced Imaging When Indicated

• Proceed to MRI with MRCP if ultrasound is negative but ALP remains elevated, as MRCP demonstrates 86% sensitivity and 94% specificity for PSC and is superior for detecting intrahepatic biliary abnormalities, small duct disease, and partial obstruction 1
• If common bile duct stones are demonstrated on ultrasound, proceed directly to ERCP for therapeutic intervention 1

Step 4: Serologic Testing Based on Clinical Context

• Check AMA, ANA (with sp100/gp210 subtyping), ASMA, and quantitative IgG if autoimmune liver disease is suspected 1
• Consider viral hepatitis serologies (HAV, HBV, HCV) if risk factors are present 1
• In inflammatory bowel disease patients with elevated ALP, obtain high-quality MRCP to evaluate for primary sclerosing cholangitis 1

Step 5: Bone Workup When GGT is Normal

• Measure bone-specific ALP if available, as it is a sensitive marker for bone turnover and metastases 1
• Order bone scan only if localized bone pain, constitutional symptoms, or radiographic findings suggest bone pathology 1
• In chronic kidney disease patients, measure intact PTH, calcium, and phosphorus to assess for renal osteodystrophy, as elevated PTH plus elevated ALP strongly suggests high-turnover bone disease 1

Critical Pitfalls to Avoid

• Do not assume NASH is the cause when ALP ≥2× ULN, as NASH typically elevates ALT more than ALP 1
• Do not rely on normal ultrasound to exclude intrahepatic cholestasis or PSC—MRCP is mandatory when clinical suspicion persists 1
• Do not delay MRCP while awaiting serology results; order both concurrently to expedite diagnosis 1
• Do not overlook medication review, particularly in older patients where drug-induced cholestasis comprises up to 61% of cases 1
• Do not underestimate sepsis as a cause of extremely high ALP (>1000 U/L) even when bilirubin is normal 3
• Do not forget malignancy—in patients with unexplained isolated ALP elevation, 57% have underlying malignancy, most commonly hepatic or bone metastases 2

Special Population Considerations

• Patients ≥80 years with markedly elevated ALP and normal ultrasound require simultaneous MRCP and autoimmune serologies (AMA, ANA with sp100/gp210) to screen for PBC, PSC, or cholangiocarcinoma 1
• Postmenopausal women with mild ALP elevation and no symptoms are unlikely to have bone metastases; bone scan is not recommended without clinical symptoms 1
• Patients under 40 years with suspected bone pathology may require urgent referral to a bone sarcoma center 1
• Chronic kidney disease patients with isolated ALP elevation most commonly have renal osteodystrophy; measure PTH, calcium, and phosphorus rather than pursuing hepatobiliary workup 1