What are the causes of elevated alkaline phosphatase (alkphos) with normal liver function tests (LFT)?

Elevated Alkaline Phosphatase with Normal Liver Function Tests

The most common causes of isolated elevated alkaline phosphatase with normal LFTs are bone disorders (Paget's disease, bone metastases, fractures), infiltrative liver diseases (hepatic metastases, amyloidosis, sarcoidosis), cholestatic liver diseases (primary biliary cholangitis, primary sclerosing cholangitis), and partial biliary obstruction—with malignancy accounting for 57% of cases in one large cohort. 1

Initial Diagnostic Step: Confirm the Source

Measure gamma-glutamyl transferase (GGT) immediately to determine whether the elevated ALP originates from liver or bone. 2, 3

• Elevated GGT confirms hepatobiliary origin and indicates cholestasis, as GGT is found in liver, kidneys, intestine, prostate, and pancreas but not in bone 2
• Normal GGT suggests bone or other non-hepatic sources (bone disease, intestinal ALP, or benign familial hyperphosphatasemia) 3
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone 3

Hepatobiliary Causes (When GGT is Elevated)

Cholestatic Liver Diseases

• Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most common chronic cholestatic conditions causing persistent ALP elevation 4
• Drug-induced cholestasis is particularly common in older patients, comprising up to 61% of cholestatic liver injury cases in patients ≥60 years 3
• Review all medications meticulously, as this is a reversible cause 4

Biliary Obstruction

• Choledocholithiasis is the most common cause of extrahepatic biliary obstruction, occurring in approximately 18% of adults undergoing cholecystectomy 2, 4
• Malignant obstruction from pancreatic cancer, cholangiocarcinoma, or ampullary tumors 2
• Biliary strictures from prior surgery, chronic pancreatitis, or infections 2

Infiltrative Liver Diseases

• Hepatic metastases are a leading cause of isolated elevated ALP—in one study, 61 patients had infiltrative intrahepatic malignancy, 52 had bony metastasis, and 34 had both 1
• Non-malignant infiltrative diseases including amyloidosis and sarcoidosis 3, 4
• These can present with isolated ALP elevation even when standard LFTs (ALT, AST, bilirubin) remain normal 3

Other Hepatic Causes

• Cirrhosis can cause ALP elevation from intrahepatic cholestasis, though this typically occurs with abnormal albumin 4
• Chronic hepatitis, viral hepatitis, and congestive heart failure (hepatic congestion) 2
• Ischemic cholangiopathy 2

Critical Pitfall

Do not attribute ALP elevation ≥2× upper limit of normal to nonalcoholic steatohepatitis (NASH), as this is atypical for NASH and suggests alternative pathology. 3, 4

Bone Causes (When GGT is Normal)

Primary Bone Disorders

• Paget's disease of bone causes markedly elevated ALP, often >1000 U/L 2, 5
• Bone metastases from breast, prostate, lung, or other primary malignancies 2, 1
• Fractures (healing fractures cause transient ALP elevation) 2
• Osteomalacia with classical biochemical changes including hypocalcemia, hypophosphatemia, increased PTH, and elevated bone ALP 3

Physiologic Causes

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

Bone-Specific Testing

• Bone-specific ALP (B-ALP) measurement can be useful when bone origin is suspected, as it is a sensitive marker for bone turnover and bone metastases 3, 6
• Bone scan is indicated for patients with localized bone pain or clinical symptoms suggesting bone pathology 3

Imaging Algorithm for Hepatobiliary Workup

First-Line Imaging

Perform abdominal ultrasound as the first-line imaging modality to assess for dilated intra- or extrahepatic ducts, gallstones, infiltrative lesions, or masses. 2, 3, 4

• Ultrasound can identify choledocholithiasis, biliary dilation, and hepatic masses 2
• If common bile duct stones are demonstrated on ultrasound, proceed directly to ERCP 3

Second-Line Imaging

If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP, which is superior to CT for detecting intrahepatic biliary abnormalities, primary sclerosing cholangitis, and small duct disease. 3, 4

• MRI/MRCP is particularly useful for identifying choledocholithiasis, biliary strictures, infiltrative diseases, and early PSC 3
• Normal CT does not exclude intrahepatic cholestasis 3

Special Populations

In patients with inflammatory bowel disease and elevated ALP, obtain high-quality MRCP to evaluate for primary sclerosing cholangitis. 3, 4

• If MRCP is normal but PSC is still suspected, consider liver biopsy to diagnose small-duct PSC 3

Severity Classification and Urgency

The American College of Gastroenterology defines severity as: 3

• Mild elevation: <5× upper limit of normal (ULN)
• Moderate elevation: 5-10× ULN
• Severe elevation: >10× ULN

Severe elevation (>10× ULN) requires expedited workup given its high association with serious pathology, including malignancy, sepsis, and severe biliary obstruction. 3, 5

Additional Laboratory Workup

When hepatobiliary origin is confirmed:

• Fractionate total bilirubin to determine the percentage of direct (conjugated) bilirubin 3, 4
• Check viral hepatitis serologies (HAV IgM, HBsAg, HBc IgM, HCV antibody) if risk factors are present 3
• Measure autoimmune markers (ANA, ASMA, AMA, IgG levels) if autoimmune liver disease is suspected 3
• Assess albumin and PT/INR to evaluate hepatic synthetic function 3

Rare and Uncommon Causes

• Sepsis: Can cause extremely high ALP (>1000 U/L) with normal bilirubin, particularly with gram-negative organisms, gram-positive organisms, or fungal infections 5
• Benign familial hyperphosphatasemia: Inherited condition with markedly elevated intestinal ALP (29-44% of total) 7
• X-linked hypophosphatemia (XLH): Presents with elevated ALP, hypophosphatemia, and elevated FGF23 3
• Common variable immunodeficiency (CVID): Approximately 40% have abnormal LFTs, with increased ALP the most frequent abnormality 3

Follow-Up Strategy

If initial evaluation is unrevealing, repeat ALP measurement in 1-3 months and monitor closely if ALP continues to rise, as persistent elevation warrants further investigation. 3

• In one study, 47% of patients with isolated elevated ALP of unclear etiology died within an average of 58 months, highlighting the clinical significance of this finding 1