What is the cause of elevated alkaline phosphatase (ALP) with normal liver enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT)) and bilirubin levels in an adult patient?

Elevated Alkaline Phosphatase with Normal Liver Enzymes and Bilirubin

Primary Differential Diagnosis

An isolated alkaline phosphatase of 340 U/L with normal AST, ALT, and bilirubin most commonly indicates either bone disease, infiltrative liver disease (particularly malignancy), or early cholestatic disease that has not yet affected bilirubin levels. 1

The first critical step is confirming the hepatic origin by measuring GGT or obtaining ALP isoenzyme fractionation, as ALP commonly originates from bone, intestine, or placenta rather than liver 1. If GGT is elevated, this confirms hepatobiliary origin; if GGT is normal, this suggests bone or other non-hepatic sources 1.

Hepatobiliary Causes (If GGT is Elevated)

Most Common Etiologies

• Infiltrative liver disease - particularly malignancy (hepatic metastases, lymphoma) - is the most common cause of isolated ALP elevation in hospitalized patients, accounting for 57% of cases in one study 2
• Primary biliary cholangitis (PBC) - typically presents with ALP 2-10× ULN with positive antimitochondrial antibody 1
• Primary sclerosing cholangitis (PSC) - ALP typically ≥1.5× ULN, strongly associated with inflammatory bowel disease 1
• Partial bile duct obstruction - from choledocholithiasis, biliary strictures, or early malignant obstruction that hasn't yet elevated bilirubin 1
• Drug-induced cholestasis - particularly in older patients (comprises up to 61% of cholestatic drug injury in patients ≥60 years) 1
• Sepsis/bacteremia - can cause extreme ALP elevation (>1000 U/L) even with normal bilirubin in 70% of cases 3, 4

Diagnostic Algorithm for Hepatobiliary Origin

1. Obtain abdominal ultrasound immediately as first-line imaging to assess for:

   • Dilated intrahepatic or extrahepatic ducts 1
   • Infiltrative liver lesions or masses 1
   • Gallstones or choledocholithiasis 1
   • Sensitivity: 65-95% for biliary obstruction, 98% positive predictive value for liver parenchymal disease 5

2. If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP, which is superior to CT for detecting:

   • Intrahepatic biliary abnormalities 1
   • Primary sclerosing cholangitis 1
   • Small duct disease 1
   • Partial bile duct obstruction not visible on ultrasound 1

3. Check autoimmune markers if imaging is unrevealing:

   • Antimitochondrial antibody (AMA) for PBC 1
   • ANA, ASMA, and IgG levels for autoimmune overlap syndromes 1

4. Review all medications against the LiverTox® database, as drug-induced cholestasis is common, especially in older patients 1

Non-Hepatic Causes (If GGT is Normal)

Bone-Related Causes

• Paget's disease of bone 1
• Bone metastases - accounted for 52 patients (20%) in one study of isolated ALP elevation 2
• Fractures (healing phase) 1
• Osteomalacia - particularly with vitamin D deficiency 1

Diagnostic Approach for Bone Origin

• Measure bone-specific ALP (B-ALP) if available - sensitive marker for bone turnover and metastases 1
• Obtain bone scan only if localized bone pain or clinical suspicion for metastases 1
• Consider age and sex - ALP levels are physiologically 2-3× adult values in children due to bone growth 1, and postmenopausal women may have elevated ALP from osteoporosis 1

Critical Clinical Pitfalls

• Do not assume isolated ALP elevation is benign - 47% of patients with unexplained isolated ALP elevation died within an average of 58 months, with malignancy being the most common cause 2
• Normal bilirubin does NOT exclude significant hepatobiliary disease - sepsis and infiltrative disease commonly present with extreme ALP elevation (>1000 U/L) and normal bilirubin 3, 4
• Do not attribute ALP ≥2× ULN to NASH - this is atypical for NASH, which primarily elevates ALT 1
• Transient ALP elevations (normalizing within 1-3 months) occur in 52% of hospitalized patients and are often associated with congestive heart failure or benign bone disease 6
• Persistent ALP elevation (>3 months) is associated with clinically obvious life-threatening diagnoses in 57% of cases 6

Monitoring Strategy

• If initial workup is unrevealing, repeat ALP measurement in 1-3 months 1
• If ALP continues to rise, intensify evaluation with cross-sectional imaging and consider hepatology referral 1
• If ALP >3× baseline without alternative explanation, consider drug interruption if on potentially hepatotoxic medications 1
• Calculate FIB-4 score to assess risk of advanced fibrosis if chronic liver disease is suspected 1