What does alkaline phosphatase (ALP) indicate, what are normal adult serum values, and what conditions cause elevated or low levels?

Alkaline Phosphatase (ALP): Clinical Significance and Diagnostic Approach

Alkaline phosphatase is an enzyme primarily derived from liver and bone that, when elevated, most commonly indicates cholestatic liver disease, biliary obstruction, infiltrative liver disease (especially metastases), or bone disorders—while low levels suggest hypophosphatasia, malnutrition, or antiresorptive drug therapy. 1

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Normal Adult Serum Values

• Normal adult ALP ranges approximately 40–130 IU/L, though reference ranges vary by laboratory and methodology. 1
• Physiologic elevations occur in childhood (2–3× adult values due to bone growth) and pregnancy (placental production in second and third trimesters). 1

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Elevated Alkaline Phosphatase: Causes and Diagnostic Strategy

Step 1: Confirm Hepatobiliary vs. Bone Origin

• Measure gamma-glutamyl transferase (GGT) concurrently with ALP. Elevated GGT confirms hepatobiliary origin; normal GGT suggests bone or other non-hepatic sources. 1
• If GGT is unavailable, obtain ALP isoenzyme fractionation to quantify the percentage derived from liver versus bone. 1

Step 2: Severity Classification Guides Urgency

Severity	ALP Level	Clinical Implication
Mild	<5× ULN	Routine workup over 1–3 months [1]
Moderate	5–10× ULN	Expedited imaging and laboratory evaluation [1]
Severe	>10× ULN	Urgent workup for serious pathology (malignant obstruction, sepsis, complete biliary blockage) [1]

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Hepatobiliary Causes of Elevated ALP

Primary Cholestatic Liver Diseases

• Primary biliary cholangitis (PBC): Diagnosis requires elevated ALP plus positive antimitochondrial antibody (AMA); ALP typically 2–10× ULN. 1, 2
• Primary sclerosing cholangitis (PSC): ALP ≥1.5× ULN; strongly associated with inflammatory bowel disease (50–80% of cases). Abrupt ALP spikes suggest transient obstruction from inflammation, bacterial cholangitis, sludge, or stones. 1, 2

Biliary Obstruction

• Choledocholithiasis: Present in ~18% of adults undergoing cholecystectomy; causes cholestasis and elevated ALP. 1, 2
• Malignant obstruction, biliary strictures, and infections are major extrahepatic causes. 1, 2

Infiltrative Liver Disease

• Hepatic metastases are the leading cause of isolated ALP elevation, accounting for 57% of cases in one large cohort. 3
• Non-malignant infiltrative diseases include amyloidosis and sarcoidosis. 1, 2

Other Hepatobiliary Conditions

• Cirrhosis and chronic hepatitis cause ALP elevation from intrahepatic cholestasis and architectural distortion. 1, 2
• Congestive heart failure can elevate ALP. 1
• Drug-induced cholestasis is especially common in older adults, comprising up to 61% of cholestatic liver injury in patients ≥60 years. 1

Important Caveat

• ALP elevation ≥2× ULN is atypical in non-alcoholic steatohepatitis (NASH); NASH typically elevates ALT more than ALP. 1, 2

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Bone Causes of Elevated ALP

• Paget's disease, bony metastases, and fractures are significant sources. 1
• Elevated ALP in postmenopausal women is mainly caused by high bone turnover; bisphosphonate therapy lowers ALP by reducing bone turnover. 4
• Bone-specific ALP (B-ALP) is a sensitive marker for bone turnover and metastases. 1

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Diagnostic Imaging Algorithm

First-Line: Abdominal Ultrasound

• Perform abdominal ultrasound to assess for dilated intra/extrahepatic ducts, gallstones, infiltrative lesions, or masses. 1, 2
• If ultrasound shows common bile duct stones, proceed directly to ERCP for diagnosis and therapeutic intervention. 1

Second-Line: MRI with MRCP

• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP, which is superior to CT for detecting intrahepatic biliary abnormalities, PSC, small-duct disease, and partial bile duct obstruction. 1, 2
• In PSC patients with abrupt ALP elevations, MRCP or ERCP is essential to evaluate for dominant strictures and cholangiocarcinoma. 1, 2

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Laboratory Workup for Hepatobiliary ALP Elevation

• Fractionate total bilirubin to determine the percentage of direct (conjugated) bilirubin; elevation confirms cholestasis. 1, 2
• Obtain complete liver panel including ALT, AST, albumin, and INR. 1
• Calculate the R value: (ALT/ULN)/(ALP/ULN). Cholestatic pattern = R ≤2; mixed = R >2 and <5; hepatocellular = R ≥5. 1
• Check autoimmune markers (AMA, ANA, ASMA, IgG) if autoimmune liver disease is suspected. 1
• Consider viral hepatitis serologies (HAV, HBV, HCV) if risk factors are present. 1
• In patients with inflammatory bowel disease and elevated ALP, obtain high-quality MRCP to evaluate for PSC. 1, 2

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Bone Workup for Non-Hepatic ALP Elevation

• Bone scan is indicated for localized bone pain, accompanying bone symptoms, or radiographic findings suggestive of bone pathology. 1
• In postmenopausal women with elevated ALP and no symptoms, bone metastases are less likely with mild elevation. 1
• Patients under 40 years with suspected bone pathology may require urgent referral to a bone sarcoma center. 1

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Low Alkaline Phosphatase: Causes and Significance

Genetic Cause

• Hypophosphatasia (pathogenic variants in ALPL gene) is the most common genetic cause; presents with bone hypomineralization, skeletal pain, chondrocalcinosis, dental problems, and stress fractures in adults. 5

Acquired Causes

• Malnutrition, vitamin and mineral deficiencies, endocrine disorders. 5
• Antiresorptive medications (bisphosphonates, denosumab) lower ALP by reducing bone turnover. 1, 6

Wilson Disease

• Markedly subnormal serum ALP (typically <40 IU/L) in acute liver failure is characteristic of Wilson disease, alongside Coombs-negative hemolytic anemia, coagulopathy, and modest aminotransferase elevations (<2000 IU/L). A ratio of ALP to total bilirubin <2 strongly suggests Wilson disease. 6

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Special Clinical Contexts

Chronic Kidney Disease

• Elevated ALP in CKD patients on dialysis predicts fracture risk and indicates high-turnover bone disease (osteitis fibrosa) when combined with elevated PTH. 1

Pregnancy

• Mild ALP elevations are physiologic in the second and third trimesters due to placental production; ALT, AST, bilirubin, and bile acids should remain normal. 1
• If pruritus and bile acids >10 µmol/L are present, diagnose intrahepatic cholestasis of pregnancy. 1

Older Adults

• Cholestatic drug-induced liver injury comprises up to 61% of cases in patients ≥60 years; meticulous medication review is essential. 1, 2

Immune Checkpoint Inhibitor Therapy

• ALP rise to ≥2× ULN in patients with normal baseline warrants evaluation for cholestatic immune-mediated liver injury, tumor progression, biliary obstruction, or drug-induced injury. 1

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Follow-Up and Monitoring

• If initial evaluation is unrevealing, repeat ALP in 1–3 months and monitor closely if ALP continues to rise. 1
• Cholestatic injury improves more slowly than hepatocellular injury; blood tests typically return to baseline within 6 months after removing the offending agent. 1
• In PSC, falling ALP (normalization or <1.5× ULN) stratifies for improved outcome, independent of therapy. 1

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Critical Pitfalls to Avoid

• Do not assume NASH is the cause of ALP ≥2× ULN; NASH typically elevates ALT more than ALP. 1
• Do not delay MRCP while awaiting serology results; order both concurrently to expedite diagnosis. 1
• Normal ultrasound does not exclude intrahepatic cholestasis, PSC, or small-duct disease; MRCP is mandatory if ALP remains elevated. 1
• Do not underestimate biliary sludge; it is a precursor to stones and can cause obstruction. 1
• In acute choledocholithiasis, ALT can surpass ALP, mimicking acute hepatitis; do not assume elevated transaminases exclude biliary obstruction. 1