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

Causes of Elevated Alkaline Phosphatase

Elevated ALP most commonly originates from cholestatic liver diseases, biliary obstruction, infiltrative liver disease (particularly malignancy), bone disorders, and sepsis. 1

Hepatobiliary Causes

Primary Cholestatic Liver Diseases

• Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most common chronic cholestatic conditions causing persistent ALP elevation, typically ranging 2-10× ULN for PBC and ≥1.5× ULN for PSC. 1, 2
• PSC characteristically presents with episodes of cholangitis causing abrupt elevations of ALP, total bilirubin, and aminotransferases, which may reflect transient obstruction from inflammation, bacterial cholangitis, sludge, or choledocholithiasis. 2
• In patients with inflammatory bowel disease and elevated ALP, PSC should be strongly suspected and high-quality MRCP is the recommended diagnostic test. 1, 2

Biliary Obstruction

• Extrahepatic biliary obstruction from choledocholithiasis, malignant obstruction, and biliary strictures are major causes of ALP elevation. 1, 2
• Approximately 18% of adults undergoing cholecystectomy have choledocholithiasis, which significantly impacts liver function tests. 1, 2
• When gallstones migrate to the common bile duct, they cause partial or complete biliary obstruction, leading to cholestasis and elevated ALP. 1

Infiltrative Liver Diseases

• Infiltrative diseases, particularly hepatic metastases, are a leading cause of isolated elevated ALP. 2
• In a retrospective study of 260 patients with isolated elevated ALP of unknown etiology, 57% had underlying malignancy (61 with infiltrative intrahepatic malignancy, 52 with bony metastasis, 34 with both). 3
• Non-malignant infiltrative diseases including amyloidosis and sarcoidosis also cause isolated ALP elevation. 1, 2

Other Hepatic Conditions

• Cirrhosis represents the most frequent condition causing both elevated ALP and hypoalbuminemia simultaneously, as the liver loses synthetic capacity and develops cholestatic features. 2
• Chronic hepatitis progressing to cirrhosis demonstrates ALP elevation from intrahepatic cholestasis. 1, 2
• Drug-induced cholestasis is a common reversible cause, particularly in older patients where it comprises up to 61% of cases in patients ≥60 years. 1, 2
• Congestive heart failure is associated with ALP elevation. 1

Sepsis-Related Cholestasis

• Sepsis is a major cause of extremely high ALP elevations (>1,000 U/L). 4
• In one study of 37 hospitalized patients with ALP >1,000 U/L, 10 had sepsis as the cause, including gram-negative organisms, gram-positive organisms, and fungal sepsis. 4
• Patients with sepsis can have extremely high ALP levels with normal bilirubin, which is a critical diagnostic pitfall to recognize. 4

Non-Hepatic Causes

Bone Disorders

• Bone disorders including Paget's disease, bony metastases, and fractures are significant sources of ALP elevation. 1
• In the study of isolated elevated ALP, 29% had bone disease as the cause. 3
• Raised ALP in prostate cancer patients with bone metastases is associated with increased osteoblastic activity. 1

Physiologic Causes

• Childhood: ALP levels are physiologically 2-3× adult values due to bone growth. 1
• Pregnancy: ALP can be elevated due to placental production. 1
• Postmenopausal women: Elevated ALP may originate from bone due to osteoporosis rather than liver disease. 1

Intestinal ALP

• Benign familial intestinal hyperphosphatasemia (BFIH) can cause persistent elevations of intestinal ALP without underlying pathology. 5
• This is a rare but important entity to recognize to avoid unnecessary additional studies. 5

Severity Classification

The severity of ALP elevation guides diagnostic urgency and differential diagnosis: 1, 2

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

Diagnostic Approach

Initial Confirmation

• First, confirm hepatobiliary origin by measuring GGT—elevated GGT confirms liver source while normal GGT suggests bone disease. 1, 2
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage from liver versus bone. 1, 2

Hepatobiliary Workup

• Perform abdominal ultrasound as first-line imaging to assess for dilated ducts, gallstones, infiltrative lesions, or masses. 1, 2
• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP, which is superior for detecting intrahepatic biliary abnormalities, PSC, small duct disease, and partial bile duct obstruction. 1, 2
• Review medication history meticulously, particularly in older patients, as drug-induced cholestasis is a common reversible cause. 1, 2

Additional Laboratory Tests

• Fractionate total bilirubin to determine the percentage of direct bilirubin, which helps differentiate cholestatic patterns. 1, 2
• Obtain complete liver panel including ALT, AST, total and direct bilirubin, and albumin. 1
• Consider viral hepatitis serologies (HAV, HBV, HCV) if risk factors are present. 1
• Measure ANA, ASMA, AMA, and IgG levels if autoimmune disease is suspected. 1

Critical Pitfalls to Avoid

• Do not assume NASH is the cause of ALP elevation ≥2× ULN, as NASH typically causes ALT elevation more than ALP and is an unlikely cause of significantly elevated ALP. 1, 2
• Do not underestimate sepsis as a cause, especially when ALP is extremely elevated with normal bilirubin. 4
• In patients with known HPP (hypophosphatasia), recognize that ALP can increase due to concurrent liver disease, potentially masking the diagnosis. 6
• Normal CT does not exclude intrahepatic cholestasis; MRI/MRCP is more sensitive for biliary tree evaluation. 1

Prognostic Significance

• In the study of isolated elevated ALP of unclear etiology, 47% of patients died within an average of 58 months after identification, highlighting the potential clinical significance of this finding. 3
• An isolated, elevated ALP of unclear etiology is most commonly associated with metastatic intrahepatic malignancy and uncommonly associated with primary parenchymal liver disease. 3