What causes elevated alkaline phosphatase (alk phos) levels?

Causes of Elevated Alkaline Phosphatase

Primary Hepatobiliary Causes

Elevated alkaline phosphatase most commonly originates from hepatobiliary disease, bone disorders, or systemic conditions like sepsis, with the specific etiology varying by clinical context and degree of elevation. 1

Cholestatic Liver Diseases

• Primary biliary cholangitis, primary sclerosing cholangitis, drug-induced cholestasis, and partial bile duct obstruction are major causes of chronic ALP elevation 1
• In patients with inflammatory bowel disease, elevated ALP should raise immediate suspicion for primary sclerosing cholangitis 1
• Overlap syndromes (AIH/PBC or AIH/PSC) should be considered when serum alkaline phosphatase is more than mildly elevated and does not normalize rapidly with immunosuppressive treatment 2

Biliary Obstruction

• Extrahepatic biliary obstruction from choledocholithiasis, malignant obstruction, biliary strictures, and infections are critical causes 1
• Approximately 18% of adults undergoing cholecystectomy have choledocholithiasis, which can significantly impact liver function tests 1
• Malignant biliary obstruction is particularly common in hospitalized patients with extremely high ALP levels (>1000 IU/L) 3, 4

Infiltrative Liver Disease

• Hepatic metastases and amyloidosis cause chronic ALP elevation through infiltrative processes 1
• In one large study, underlying malignancy accounted for 57% of isolated elevated ALP cases, with 61 patients having infiltrative intrahepatic malignancy 5
• Diffuse liver metastases can produce extremely high ALP levels without proportional bilirubin elevation 3

Other Hepatic Conditions

• Cirrhosis, chronic hepatitis, viral hepatitis, and congestive heart failure are associated with ALP elevation 1
• 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) 1

Sepsis and Infectious Causes

Sepsis is a frequently overlooked cause of extremely high ALP elevation, often with normal bilirubin levels. 3

• In hospitalized patients with ALP >1000 IU/L, sepsis (including gram-negative, gram-positive, and fungal organisms) was the most common cause in one series 3
• Seven of 10 patients with sepsis had extremely high alkaline phosphatase with normal bilirubin, a critical diagnostic pattern 3
• In AIDS patients, mycobacterium avium intracellulare (MAI) infection and cytomegalovirus infection are important causes 3
• Cholangiocarcinoma and tropical diseases unique to certain geographic settings can produce marked ALP elevation 4

Bone-Related Causes

Malignant Bone Disease

• Bony metastases are a significant source of ALP elevation, particularly in patients with known malignancy 1
• In one study, 52 patients had bony metastasis alone, and 34 had both hepatic and bone metastasis as causes of elevated ALP 5
• Bone-specific ALP (B-ALP) is a sensitive marker for bone turnover and bone metastases 1

Benign Bone Disorders

• Paget's disease produces extremely high ALP levels and shows excellent correlation between B-ALP and total ALP (r² = 0.94) 6
• Fractures can cause transient ALP elevation 1
• Bone disease accounted for 29% of isolated elevated ALP cases in one large cohort 5

Physiologic Causes

• Childhood and pregnancy are normal physiologic states with elevated ALP 1
• ALP levels are physiologically higher in childhood due to bone growth 1
• Pregnancy causes elevation due to placental production 1
• B-ALP increases by 77% after menopause compared to only 24% increase in total ALP, making B-ALP more sensitive for detecting postmenopausal bone changes 6

Drug-Induced Causes

• Older patients (≥60 years) are particularly prone to cholestatic drug-induced liver injury, which can comprise up to 61% of cases in this age group 1
• Glucocorticoids and anticonvulsants can induce ALP elevation 7
• Dilantin toxicity has been reported as a cause of extremely high ALP 3
• Review of medication history is crucial to identify potential drug-induced causes 1

Less Common Causes

• Sarcoid hepatitis can produce elevated ALP 3
• Lead toxicity is a rare but important cause 3
• Liver hemangiomas may cause elevation 3
• Approximately 40% of patients with common variable immunodeficiency (CVID) have abnormalities in liver function tests, with increased ALP the most frequent abnormality 1

Diagnostic Approach by Severity

Mild Elevation (<5× ULN)

• Measure GGT concurrently to confirm hepatobiliary origin; normal GGT suggests bone or other non-hepatic sources 1
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation 1
• Consider bone-specific ALP measurement for suspected bone origin 1

Moderate to Severe Elevation (≥5× ULN)

• Severe elevation (>10× ULN) requires expedited workup given high association with serious pathology including malignancy, sepsis, and biliary obstruction 1, 3, 5
• Perform abdominal ultrasound as first-line imaging to assess for dilated ducts and gallstones 1
• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP 1
• Consider viral hepatitis serologies if risk factors are present 1

Critical Clinical Pitfalls

• Do not attribute isolated ALP elevation ≥2× ULN to NASH, as this is atypical for non-alcoholic steatohepatitis 1
• Treatments like bisphosphonates and denosumab can alter ALP levels despite underlying pathology 1
• Bone-specific ALP is less useful in chronic liver disease because it is difficult to measure accurately when liver ALP is elevated 1
• An isolated elevated ALP of unclear etiology carries significant mortality risk: 47% of patients died within an average of 58 months after identification in one study 5