What causes elevated alkaline phosphatase (alk phos) with normal liver function tests (LFTs) and normal calcium levels?

Elevated Alkaline Phosphatase with Normal LFTs and Normal Calcium

When alkaline phosphatase is elevated in isolation with normal liver enzymes and normal calcium, the most common causes are bone disorders (Paget's disease, bone metastases, fractures), benign familial hyperphosphatasemia, or early cholestatic liver disease that has not yet affected other liver markers. 1

Initial Diagnostic Step: Confirm the Source

The first critical step is to measure gamma-glutamyl transferase (GGT) concurrently with the elevated ALP 1:

• Elevated GGT confirms hepatobiliary origin 1, 2
• Normal GGT strongly 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

If Hepatobiliary Origin (Elevated GGT)

First-Line Imaging

Perform abdominal ultrasound as the initial imaging modality to assess for 3, 1:

• Dilated intrahepatic or extrahepatic bile ducts
• Gallstones or choledocholithiasis (present in ~18% of adults undergoing cholecystectomy) 1
• Infiltrative liver lesions or masses
• Signs of cirrhosis

If Ultrasound is Negative but ALP Remains Elevated

Proceed to MRI with MRCP, which is superior to ultrasound and CT for detecting 1, 2:

• Intrahepatic biliary abnormalities
• Primary sclerosing cholangitis (especially if inflammatory bowel disease is present) 1, 2
• Small duct disease
• Choledocholithiasis and biliary strictures 1

Key Hepatobiliary Causes to Consider

Primary cholestatic liver diseases 1, 2:

• Primary biliary cholangitis (PBC)
• Primary sclerosing cholangitis (PSC) - particularly suspect if patient has inflammatory bowel disease 1, 2
• Drug-induced cholestasis (review medications meticulously, especially in older patients where this comprises up to 61% of cases) 1

Biliary obstruction 1, 2:

• Choledocholithiasis
• Malignant obstruction
• Biliary strictures

Infiltrative diseases 1, 2:

• Hepatic metastases (a leading cause of isolated elevated ALP) 2
• Sarcoidosis 1
• Amyloidosis 1

Other hepatic causes 1, 2:

• Sepsis (can cause extremely high ALP with normal bilirubin) 4
• Early cirrhosis
• Chronic hepatitis

Important Caveat

Do not attribute ALP elevation ≥2× upper limit of normal to nonalcoholic steatohepatitis (NASH), as this is atypical for NASH, which typically causes ALT elevation more than ALP 1

If Bone Origin (Normal GGT)

Clinical Assessment

Evaluate for 1:

• Localized bone pain - warrants targeted imaging or bone scan 1
• Recent fractures 1
• History of malignancy - bone metastases are a significant source 1

Bone-Specific Testing

Consider bone-specific alkaline phosphatase (B-ALP) measurement, which is a sensitive marker for bone turnover and bone metastases 1, 5

Major Bone Causes 1:

• Paget's disease of bone
• Bone metastases (less likely with mild elevation and no symptoms) 1
• Fractures
• Osteomalacia (though typically associated with hypocalcemia and hypophosphatemia, calcium can be normal) 1

Imaging Recommendations

Bone scan is indicated when 1:

• Localized bone pain is present
• Elevated ALP suggests bone origin
• Clinical suspicion for bone metastases or Paget's disease

Patients under 40 years with suspected bone pathology may require urgent referral to a bone sarcoma center 1

Physiologic and Benign Causes

Benign Familial Hyperphosphatasemia

This is a rare but important diagnosis of exclusion characterized by 6:

• Persistently elevated ALP (often markedly elevated)
• Normal liver and bone imaging
• Family history of elevated ALP
• Increased intestinal alkaline phosphatase isoenzyme 6

Early recognition avoids unnecessary diagnostic testing 6

Physiologic Elevations 1:

• Childhood - ALP levels are physiologically higher due to bone growth
• Pregnancy - due to placental production

Severity-Based Approach

The American College of Gastroenterology classifies ALP elevation as 1:

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

Severe elevation (>10× ULN) requires expedited workup given its high association with serious pathology including malignant obstruction, sepsis, and infiltrative disease 1, 4, 7

Follow-Up for Unrevealing Initial Workup

If initial evaluation is unrevealing, repeat ALP measurement in 1-3 months and monitor closely 1. Persistent or rising ALP warrants further investigation including:

• Medication review (particularly in older patients) 1
• Consideration of less common causes (sarcoidosis, amyloidosis, benign familial hyperphosphatasemia)
• Possible liver biopsy if imaging remains negative and ALP continues to rise 1

Critical Pitfalls to Avoid

• Never assume bone disease without confirming with GGT, bone-specific ALP, or bone scan - hepatobiliary causes are common even with normal other LFTs 1
• Do not rely on CT alone - normal CT does not exclude intrahepatic cholestasis; MRI/MRCP is more sensitive for biliary tree evaluation 1
• Do not overlook drug-induced cholestasis, especially in older patients 1
• Do not attribute significant ALP elevation to NASH when ALP is ≥2× ULN 1