What are the causes of elevated alkaline phosphatase (ALP) levels?

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) is most commonly caused by hepatobiliary disorders, bone diseases, and sepsis, with malignancy being the predominant cause of significantly elevated levels in adults. 1, 2

Diagnostic Approach

When evaluating elevated ALP, it's essential to determine if the elevation is isolated or part of a pattern:

Step 1: Determine the Pattern

• Cholestatic pattern: R ≤2 [(ALT/ULN)/(ALP/ULN)]
• Mixed pattern: R >2 and <5
• Hepatocellular pattern: R ≥5 1

Step 2: Identify Source of Elevation

Hepatobiliary Causes (most common):

• Biliary obstruction
  • Malignant obstruction (cholangiocarcinoma, pancreatic cancer)
  • Benign obstruction (gallstones, strictures)
• Infiltrative liver diseases
  • Malignant (metastases, primary liver cancer)
  • Non-malignant (sarcoidosis, amyloidosis)
• Parenchymal liver diseases
  • Primary biliary cholangitis (PBC)
  • Primary sclerosing cholangitis (PSC)
  • Drug-induced liver injury
  • Viral hepatitis 1, 2

Bone Causes:

• Paget's disease
• Bone metastases
• Osteomalacia
• Rickets
• Hyperparathyroidism
• Fracture healing 1, 2

Other Significant Causes:

• Sepsis (can present with extremely high ALP and normal bilirubin)
• Malignancy (both hepatic and bone involvement)
• Pregnancy (placental origin)
• Intestinal diseases
• Hyperthyroidism
• Medication-induced (anticonvulsants, glucocorticoids) 1, 3, 4

Evaluation of Elevated ALP

Initial Laboratory Workup:

• Complete liver panel (AST, ALT, GGT, total/direct bilirubin, albumin, PT/INR)
• GGT (to confirm hepatic origin of ALP elevation)
• Viral hepatitis screening (HBsAg, HBcAb, HCV antibody)
• Metabolic workup (fasting glucose, HbA1c, lipid profile, ferritin, transferrin saturation)
• Autoimmune markers (ANA, ASMA, immunoglobulins) 1

For Suspected Bone Origin:

• Calcium, phosphate, PTH, 25(OH) vitamin D levels
• Bone-specific ALP isoenzyme testing
• Bone imaging 1

Imaging Studies:

• First-line: Abdominal ultrasound (for biliary obstruction, liver parenchymal abnormalities)
• Second-line: MRCP (detailed biliary evaluation, especially for PSC)
• Additional: CT scan, MRI, Transient Elastography (FibroScan) 1

Clinical Significance

Recent research highlights the importance of thoroughly investigating isolated ALP elevations:

• In a 2024 study, 57% of patients with isolated elevated ALP of unclear etiology had underlying malignancy 2
• 47% of patients with isolated elevated ALP died within an average of 58 months after identification 2
• Extremely high ALP levels (>1000 IU/L) are most commonly associated with sepsis, malignant obstruction, and infiltrative diseases 3, 5

Common Pitfalls and Caveats

1. Overlooking non-hepatic causes: Always consider bone disease, sepsis, and medication effects when evaluating elevated ALP 1, 4

2. Normal bilirubin with high ALP: Don't dismiss significantly elevated ALP when bilirubin is normal, as this can occur in sepsis and early infiltrative disease 3

3. Benign familial intestinal hyperphosphatasemia: A rare cause of persistent ALP elevation without underlying pathology that should be considered after excluding other causes 6

4. Age and physiological variations: ALP is naturally elevated in growing children, pregnant women, and can be influenced by high-fat diets 4

5. Medication effects: Always review medications that can induce ALP elevation (glucocorticoids, anticonvulsants) 1, 4

When evaluating elevated ALP, a systematic approach focusing on the most common etiologies (hepatobiliary, bone, and systemic diseases) will lead to accurate diagnosis and appropriate management of the underlying condition.