What are the isolated causes of an elevated alkaline phosphatase (ALP) level when AST, ALT, GGT, and bilirubin are normal?

Isolated Causes of Elevated Alkaline Phosphatase

When alkaline phosphatase is elevated but AST, ALT, GGT, and bilirubin remain normal, the most likely causes are bone disease, benign familial hyperphosphatasemia, intestinal ALP, or early infiltrative liver disease that has not yet caused cholestasis. 1

Initial Diagnostic Approach

Measure GGT or obtain ALP isoenzyme fractionation to confirm whether the elevation originates from liver versus bone. 1 Normal GGT strongly suggests a non-hepatic source, while elevated GGT confirms hepatobiliary origin. 1, 2

If GGT is Normal (Non-Hepatic Source)

Bone disease is the predominant cause when GGT is normal:

• Paget's disease of bone – causes marked ALP elevation (often >5× ULN) with normal liver enzymes 1
• Bone metastases – particularly from prostate, breast, or lung cancer; accounts for 29% of isolated ALP elevations in one cohort 3
• Fractures – healing fractures elevate bone-specific ALP 1
• Renal osteodystrophy – in chronic kidney disease patients, secondary hyperparathyroidism drives high-turnover bone disease with elevated ALP and PTH 1

Physiologic causes:

• Childhood and adolescence – ALP levels are physiologically 2-3× adult values due to bone growth 1
• Pregnancy – placental ALP production causes mild elevation in second and third trimesters, with normal aminotransferases and bilirubin 1

Benign familial hyperphosphatasemia – a rare inherited condition causing persistent intestinal ALP elevation (29-44% of total ALP) without underlying pathology; diagnosis requires isoenzyme fractionation showing elevated intestinal ALP 4, 5

Recommended workup when GGT is normal:

• Assess for bone pain, fracture history, or malignancy risk factors 1
• Consider bone-specific ALP measurement 1
• Order bone scan only if localized bone pain or clinical suspicion of metastases is present 1
• In CKD patients (GFR <60 mL/min/1.73 m²), measure intact PTH, calcium, and phosphorus to diagnose renal osteodystrophy 1

If GGT is Elevated (Hepatobiliary Source)

When GGT is elevated but bilirubin remains normal, consider early or partial biliary obstruction and infiltrative liver disease:

Infiltrative liver disease:

• Hepatic metastases – the leading cause of isolated ALP elevation in one cohort (57% of cases), with 61 patients having infiltrative intrahepatic malignancy as the sole finding 3
• Amyloidosis – causes isolated ALP elevation through hepatic infiltration 1, 2
• Sarcoidosis – granulomatous infiltration elevates ALP without overt cholestasis 1, 2

Partial or intermittent biliary obstruction:

• Choledocholithiasis – approximately 18% of adults undergoing cholecystectomy have common bile duct stones; sustained ALP elevation correlates with choledocholithiasis on MRCP 1
• Biliary strictures – benign strictures cause fluctuating ALP and bilirubin due to intermittent obstruction 1
• Primary sclerosing cholangitis (PSC) – ALP typically ≥1.5× ULN; abrupt spikes reflect transient obstruction from inflammation, sludge, or stones rather than progressive disease 1, 2

Early cholestatic liver disease:

• Primary biliary cholangitis (PBC) – diagnosis requires elevated ALP plus positive antimitochondrial antibody (AMA); ALP typically ranges 2-10× ULN 1
• Drug-induced cholestasis – accounts for up to 61% of cholestatic liver injury in patients ≥60 years; review all medications, supplements, and over-the-counter agents 1, 2

Recommended imaging when GGT is elevated:

• Abdominal ultrasound first – assess for dilated ducts, gallstones, infiltrative lesions, or masses 1, 2
• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP – superior for detecting intrahepatic biliary abnormalities, PSC, small-duct disease, and partial bile duct obstruction 1, 2
• In PSC patients with abrupt ALP elevation, obtain MRCP or ERCP – evaluate for dominant stricture and cholangiocarcinoma 1, 2

Serologic workup when hepatobiliary origin is confirmed:

• Measure AMA, ANA (with sp100/gp210 subtyping), and quantitative IgG to screen for PBC 1
• In patients with inflammatory bowel disease, high-quality MRCP is mandatory to evaluate for PSC 1, 2
• Consider viral hepatitis serologies (HAV, HBV, HCV) if risk factors are present 1

Severity-Based Urgency

Severe ALP elevation (>10× ULN) requires expedited workup due to high association with serious pathology such as malignant obstruction, complete biliary blockage, or widespread metastatic disease. 1, 2

Moderate elevation (5-10× ULN) warrants prompt imaging and laboratory evaluation within 1-2 weeks. 1

Mild elevation (<5× ULN) allows for systematic outpatient evaluation, but repeat ALP in 1-3 months if initial workup is unrevealing; rising ALP indicates progression and warrants further investigation. 1

Critical Pitfalls to Avoid

• Do not assume non-alcoholic steatohepatitis (NASH) is the cause – ALP elevation ≥2× ULN is atypical in NASH, which predominantly elevates ALT 1, 2
• Do not rely on ultrasound alone – normal ultrasound does not exclude intrahepatic cholestasis, PSC, or infiltrative disease; MRCP is essential when ALP remains elevated 1, 2
• Do not overlook medication review – drug-induced cholestasis is common and reversible, especially in older adults 1, 2
• Do not order bone scan in asymptomatic patients – in the absence of bone pain or clinical suspicion, the likelihood of positive findings is <5% 1
• Consider benign familial hyperphosphatasemia – persistent intestinal ALP elevation without pathology; early recognition avoids unnecessary testing 4, 5