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

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase results from hepatobiliary disease (cholestatic liver disorders, biliary obstruction, infiltrative processes), bone disorders (Paget's disease, metastases, fractures), physiologic states (childhood growth, pregnancy), malignancy (most commonly metastatic disease to liver or bone), sepsis, and medications—with the specific cause determined by clinical context, GGT measurement, and targeted imaging. 1

Hepatobiliary Causes

Cholestatic Liver Diseases

• Primary biliary cholangitis and primary sclerosing cholangitis are major causes of chronic ALP elevation, typically presenting with ALP levels 2-10× upper limit of normal (ULN). 1
• Primary sclerosing cholangitis demonstrates a cholestatic pattern with raised ALP and GGT in approximately 75% of patients, with ALP typically ≥1.5× ULN, and is strongly associated with inflammatory bowel disease. 1
• Drug-induced cholestasis causes ALP elevation, with older patients (≥60 years) particularly susceptible—cholestatic drug-induced liver injury comprises up to 61% of cases in this age group. 1, 2

Biliary Obstruction

• Choledocholithiasis (common bile duct stones) causes partial or complete biliary obstruction leading to cholestasis, occurring in approximately 18% of adults undergoing cholecystectomy. 1
• Malignant biliary obstruction from pancreatic cancer, cholangiocarcinoma, or metastatic disease produces marked ALP elevation. 1
• Biliary strictures and infections can cause chronic ALP elevation. 1

Infiltrative Liver Diseases

• Hepatic metastases are a leading cause—in one study of isolated elevated ALP of unclear etiology, 57% were due to underlying malignancy (61 patients with infiltrative intrahepatic malignancy, 52 with bony metastasis, 34 with both). 3
• Amyloidosis and sarcoidosis can cause isolated ALP elevation through hepatic infiltration. 1

Other Hepatic Conditions

• Cirrhosis and chronic hepatitis are associated with ALP elevation, particularly as architectural distortion develops. 1
• Congestive heart failure can cause ALP elevation through hepatic congestion. 1

Bone-Related Causes

• Paget's disease of bone is a significant source of ALP elevation, reflecting increased osteoblastic activity. 1
• Bony metastases from prostate, breast, lung, or other cancers cause elevated ALP through osteoblastic activity—raised ALP in prostate cancer patients with bone metastases is associated with increased osteoblastic activity. 1
• Fractures (acute or healing) elevate ALP through bone remodeling. 1
• Osteomalacia demonstrates classical biochemical changes including elevated bone alkaline phosphatase, though serum calcium and phosphate are often normal. 1

Infectious Causes

• Sepsis is a major cause of extremely high ALP elevations (>1000 U/L)—in one study, 10 of 31 hospitalized patients with ALP >1000 U/L had sepsis (gram-negative, gram-positive, or fungal), and 7 of these 10 had normal bilirubin. 4
• Mycobacterium avium intracellulare (MAI) and cytomegalovirus infections in AIDS patients cause ALP elevation. 4

Physiologic Causes

• Childhood and adolescence: ALP levels are physiologically 2-3× adult values due to active bone growth. 1
• Pregnancy: Placental production of ALP causes elevation, particularly in the third trimester. 1

Medication-Induced Causes

• Macrolide antibiotics (azithromycin, clarithromycin) can cause ALP elevation. 2
• Rifampin and rifabutin cause hepatitis with ALP elevation. 2
• Parenteral nutrition causes ALP elevation through chronic cholestasis in up to 65% of home parenteral nutrition patients, particularly with excessive intravenous lipid administration (>1g/kg/day). 1, 2
• Anticonvulsants (phenytoin/Dilantin) can cause drug-induced cholestasis. 4
• Glucocorticoids induce ALP elevation. 5

Endocrine and Metabolic Causes

• X-linked hypophosphatemia (XLH) presents with elevated ALP as a biochemical hallmark, along with hypophosphatemia and elevated FGF23. 1
• Hyperthyroidism can cause ALP elevation through increased bone turnover. 5

Rare and Benign Causes

• Benign familial hyperphosphatasemia is a rare inherited condition with markedly elevated intestinal ALP (29-44% of total) and sometimes elevated liver/bone/kidney ALP, requiring no treatment once diagnosed. 6
• Intestinal ALP elevation can occur with high-fat diets or in the context of benign familial intestinal hyperphosphatasemia without underlying pathology. 7, 5

Special Clinical Contexts

• Common variable immunodeficiency (CVID): Approximately 40% of patients have abnormalities in liver function tests, with increased ALP the most frequent abnormality. 1
• Chronic kidney disease on dialysis: Elevated ALP predicts fracture risk (hazard ratio 1.011 per unit increase) and should prompt bone turnover assessment. 1

Critical Diagnostic Considerations

When ALP is severely elevated (>10× ULN), the most common causes are sepsis, malignant obstruction, and AIDS-related infections—this requires expedited workup. 1, 4

Measure GGT concurrently to determine source: elevated GGT confirms hepatobiliary origin, while normal GGT suggests bone or other non-hepatic sources. 1

In patients with inflammatory bowel disease and elevated ALP, high-quality MRCP should be obtained to evaluate for primary sclerosing cholangitis. 1