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

Causes of Elevated Alkaline Phosphatase

Primary Causes by Origin

Elevated alkaline phosphatase originates from either hepatobiliary disease or bone pathology in the vast majority of cases, with malignancy (particularly metastatic disease) being the single most common cause when evaluating isolated ALP elevation of unclear etiology. 1

Hepatobiliary Causes

Cholestatic liver diseases are the predominant hepatic source of chronic ALP elevation 2:

• Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) represent the most common chronic cholestatic conditions causing persistent ALP elevation 3
• PSC characteristically presents with episodic cholangitis causing abrupt ALP spikes, which may reflect transient obstruction from inflammation, bacterial cholangitis, sludge, or choledocholithiasis 3
• In patients with inflammatory bowel disease and elevated ALP, PSC should be strongly suspected 3

Biliary obstruction accounts for a substantial proportion of cases 2:

• Choledocholithiasis (common bile duct stones) affects approximately 18% of adults undergoing cholecystectomy and significantly impacts liver function tests 3
• Malignant biliary obstruction from cholangiocarcinoma, pancreatic cancer, or metastatic disease 2
• Biliary strictures and infections 2

Infiltrative liver diseases are critical to recognize 2, 3:

• Hepatic metastases are a leading cause of isolated elevated ALP, with 57% of patients with isolated ALP elevation of unclear etiology having underlying malignancy (61 patients with infiltrative intrahepatic malignancy, 52 with bony metastasis, and 34 with both) 1
• Non-malignant infiltrative diseases including amyloidosis and sarcoidosis 2, 3

Other hepatic conditions 2:

• Cirrhosis represents the most frequent condition causing both elevated ALP and hypoalbuminemia simultaneously 3
• Chronic hepatitis progressing to cirrhosis demonstrates ALP elevation from intrahepatic cholestasis 3
• Viral hepatitis (hepatitis A, B, C) 2
• Congestive heart failure 2
• Drug-induced cholestasis, particularly in older patients where it comprises up to 61% of cases in patients ≥60 years 2

Sepsis-related cholestasis is an important and often overlooked cause 3:

• Extremely high ALP elevations (>1,000 U/L) are most frequently seen in patients with sepsis, with 10 of 31 patients in one study having sepsis as the cause 4
• Seven of 10 patients with sepsis had extremely high ALP with normal bilirubin, making this a critical diagnostic pitfall 4
• Causative organisms include gram-negative, gram-positive, and fungal pathogens 4

Bone-Related Causes

Bone disorders are significant sources of ALP elevation 2:

• Paget's disease of bone 2
• Bony metastases from malignancy, with 29% of patients with isolated ALP elevation having bone disease 1
• Fractures (healing fractures cause transient elevation) 2
• Osteomalacia with classical biochemical changes including hypocalcemia, hypophosphatemia, increased PTH, and elevated bone ALP 2

Physiologic Causes

Normal physiologic states can cause ALP elevation 2:

• Childhood and adolescence: ALP levels are physiologically 2-3× adult values due to bone growth 2
• Pregnancy: placental production causes elevation 2

Special Clinical Contexts

AIDS/HIV-related causes 4:

• Nine patients in one study had AIDS with various causes including sepsis, mycobacterium avium intracellulare (MAI) infection, cytomegalovirus infection, and drug toxicity 4

Endocrine and metabolic disorders 5:

• X-linked hypophosphatemia (XLH) presents with elevated ALP as a biochemical hallmark 2
• High-fat diets can cause nonhepatic increases 5

Benign familial conditions 6, 7:

• Benign familial hyperphosphatasemia with markedly increased intestinal ALP (29-44% of total) in all family members 6
• This represents a persistent but benign biochemical abnormality that should be recognized to avoid unnecessary testing 7

Common variable immunodeficiency (CVID) 2:

• Approximately 40% of patients have abnormalities in liver function tests, with increased ALP the most frequent abnormality 2

Wilson disease presents with unique pattern 8:

• Markedly subnormal serum ALP (typically <40 IU/L) alongside Coombs-negative hemolytic anemia, coagulopathy, and modest aminotransferase elevations 8
• A ratio of ALP to total bilirubin <2 strongly suggests Wilson disease 8

Critical Clinical Pitfalls

Do not assume NASH is the cause of ALP elevation ≥2× upper limit of normal, as NASH typically causes ALT elevation more than ALP and is an unlikely cause of significantly elevated ALP 2, 3

Medication-induced elevation requires meticulous review, particularly in older patients where drug-induced cholestasis is common and reversible 3

Antiresorptive medications (bisphosphonates, denosumab) can alter ALP levels despite underlying pathology 2, 8

Parenteral nutrition can cause ALP elevation through chronic cholestasis, with reported incidence up to 65% in home parenteral nutrition patients, particularly with excessive intravenous lipid administration (>1g/kg/day) 2

Prognostic Significance

Isolated elevated ALP of unclear etiology carries significant mortality risk: 47% of patients died within an average of 58 months after identification, emphasizing the importance of thorough evaluation 1