What does an elevated alkaline phosphatase (ALP) level mean and how is it treated?

Elevated Alkaline Phosphatase: Meaning and Treatment

An elevated alkaline phosphatase (ALP) indicates either hepatobiliary disease, bone pathology, or physiologic states, and treatment is directed at the underlying cause rather than the ALP elevation itself—there is no treatment for elevated ALP per se, only for the diseases causing it. 1

What Does Elevated ALP Mean?

Hepatic Causes

The most common pathologic causes of chronic ALP elevation include:

• Cholestatic liver diseases: Primary biliary cholangitis, primary sclerosing cholangitis, drug-induced cholestasis, and partial bile duct obstruction are major causes 1
• Biliary obstruction: Choledocholithiasis (common bile duct stones), malignant obstruction, biliary strictures, and infections 1
• Infiltrative diseases: Hepatic metastases, amyloidosis 1
• Other liver conditions: Cirrhosis, chronic hepatitis, viral hepatitis, congestive heart failure 1

Bone Causes

• Paget's disease of bone, bony metastases, and fractures are significant sources of ALP elevation 1
• Bone disorders cause elevated bone-specific ALP due to increased bone turnover 1

Physiologic Causes (Not Requiring Treatment)

• Childhood: ALP levels are physiologically higher due to bone growth 1
• Pregnancy: Elevated due to placental production 1

Severity Classification

The American College of Radiology classifies ALP elevation severity to guide diagnostic urgency 1:

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

Special Clinical Contexts

• Sepsis: Extremely high ALP elevations (>1,000 U/L) are frequently seen in sepsis, and notably, patients can have extremely high ALP with normal bilirubin 2, 3
• AIDS: Approximately 40% of patients with common variable immunodeficiency have abnormal liver function tests, with increased ALP being the most frequent abnormality 1
• Malignant obstruction: One of the three most common causes of extremely high ALP levels 2, 3

How Do You Treat Elevated ALP?

Step 1: Determine the Source (Hepatic vs. Bone)

Measure GGT (gamma-glutamyl transferase) concurrently with ALP 1:

• Elevated GGT = confirms hepatobiliary origin
• Normal GGT = suggests bone or other non-hepatic sources

If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone 1

Step 2: If Hepatic Origin Confirmed

Initial Evaluation

• Review medication history thoroughly: Older patients (≥60 years) are particularly prone to cholestatic drug-induced liver injury, which comprises up to 61% of cases in this age group 1
• Assess for symptoms: Right upper quadrant pain, fatigue, nausea, weight loss 1
• Consider viral hepatitis serologies (HAV, HBV, HCV) if risk factors are present 1

First-Line Imaging

Perform abdominal ultrasound as the first-line imaging modality to assess for dilated intra- or extrahepatic ducts and gallstones 1

If ultrasound shows common bile duct stones: Proceed directly to ERCP (endoscopic retrograde cholangiopancreatography) 1

If ultrasound is negative but ALP remains elevated: Proceed to MRI with MRCP (magnetic resonance cholangiopancreatography) 1

Special Considerations

• Inflammatory bowel disease patients: Elevated ALP should raise suspicion for primary sclerosing cholangitis; high-quality MRC is recommended 1
• If high-quality MRCP is normal in suspected PSC: Consider liver biopsy to diagnose small-duct PSC 1
• Autoimmune overlap syndrome: Check ANA, ASMA, and IgG levels before considering liver biopsy 1

Treatment of Underlying Hepatobiliary Causes

• Choledocholithiasis: ERCP with stone extraction 1
• Malignant obstruction: Biliary stenting or surgical intervention depending on tumor type and resectability 3
• Drug-induced cholestasis: Discontinue offending medication 1
• Primary biliary cholangitis/primary sclerosing cholangitis: Disease-specific medical management (ursodeoxycholic acid for PBC)
• Sepsis: Treat underlying infection with appropriate antimicrobials 2, 3

Step 3: If Bone Origin Confirmed

Diagnostic Workup

• Bone scan is indicated in patients with localized bone pain or elevated ALP suggesting bone origin 1
• For suspected malignancy: Targeted imaging based on symptoms 1

Treatment of Underlying Bone Causes

• Paget's disease: Bisphosphonates (e.g., alendronate) reduce bone turnover and decrease ALP levels by approximately 15-30% 4
• Bone metastases: Oncologic treatment plus bisphosphonates or denosumab 1
• Fractures: Orthopedic management as appropriate

Important caveat: Bisphosphonates and denosumab can alter ALP levels despite underlying pathology, so ALP may not accurately reflect disease activity in patients on these medications 1, 4

Step 4: If Initial Evaluation is Unrevealing

Repeat ALP measurement in 1-3 months and monitor closely 1:

• If ALP continues to rise, this may indicate progression of underlying disease and warrants further investigation 1
• Persistent elevation with negative ultrasound requires MRI with MRCP 1

Common Pitfalls to Avoid

• Do not attribute isolated ALP elevation ≥2× ULN to NASH: Significant ALP elevation is atypical in non-alcoholic steatohepatitis 1
• Do not overlook sepsis: Sepsis can cause extremely high ALP (>1,000 U/L) with normal bilirubin, which is an unusual pattern that might be missed 2
• Do not assume bone metastases with mild ALP elevation: Bone metastases are less likely with mild ALP elevation and no symptoms, particularly in postmenopausal women 1
• Do not order bone scan without elevated ALP: A bone scan is NOT recommended in the absence of elevated ALP, even with bone pain or radiographic findings 1
• In patients on bisphosphonates: Remember that ALP levels will be artificially lowered (by approximately 15-30% for bone-specific ALP), potentially masking disease progression 1, 4