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Quick Reference
  • Normal Range (Adults): 30-120 IU/L
  • Children/Adolescents: Up to 350 IU/L (higher due to bone growth)
  • Pregnancy (3rd trimester): Up to 2-3x normal (placental ALP)
  • SI Units: 30-120 U/L
  • Sample Type: Serum
  • Key Point: Found in liver and bone; use GGT or 5'-nucleotidase to differentiate source

Test Description

What is ALP?

Alkaline phosphatase (ALP) is a group of isoenzymes that catalyze the hydrolysis of phosphate esters in an alkaline environment.

Where is ALP Found?

ALP is found in multiple tissues with highest concentrations in:

  • Liver: Bile duct epithelium and hepatocyte canalicular membrane
  • Bone: Osteoblasts (bone-forming cells)
  • Intestine: Intestinal mucosa
  • Placenta: During pregnancy
  • Kidneys: Renal tubules

Why Does ALP Increase?

  • In the liver: Cholestasis (impaired bile flow) or increased enzyme synthesis
  • In bone: Increased osteoblast activity (bone formation and turnover)
  • Clinical challenge: Determining which tissue source is causing the elevation

Isoenzyme Differentiation

ALP exists as tissue-specific isoenzymes that can be differentiated by electrophoresis or heat stability testing. The main isoenzymes are:

  • Liver ALP (ALP-1): Heat labile, elevated in cholestatic disorders
  • Bone ALP (ALP-2): Heat stable, elevated in bone disease and growth
  • Intestinal ALP: Appears after fatty meals in blood types O and B
  • Placental ALP: Elevated in pregnancy, especially 3rd trimester

In clinical practice, rather than measuring isoenzymes directly, GGT or 5'-nucleotidase can be ordered to confirm hepatic origin. If ALP is elevated and GGT/5'-NT is also elevated, the source is likely hepatobiliary. If ALP is elevated but GGT/5'-NT is normal, consider bone or other sources.

Normal Ranges

ALP reference ranges vary significantly by age due to bone growth and remodeling. Laboratory assays also differ, so local reference ranges should be consulted.

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Age/Population Normal Range (IU/L) Notes
Adults (20-60 years) 30-120 Standard adult reference range
Elderly (>60 years) Up to 130 Slightly higher due to bone turnover
Children (1-9 years) 145-320 Higher due to bone growth
Adolescents (10-18 years) 100-350 Peak during growth spurts
Pregnancy (1st/2nd trimester) 30-120 Usually normal early in pregnancy
Pregnancy (3rd trimester) Up to 240-360 Placental isoenzyme production

Important Considerations

ALP reference ranges are highly assay-dependent. Different laboratories may use different methodologies and report different normal ranges.

  • Always interpret ALP in the context of patient age, sex, and pregnancy status
  • Children and adolescents normally have ALP levels 2-3 times higher than adults
  • Bone growth spurts in puberty can cause ALP >500 IU/L without disease
  • Pregnancy-related elevations are physiologic and not concerning in isolation
  • Blood type O individuals may have mild elevations after fatty meals (intestinal ALP)
Clinical Significance

Elevated ALP (Hyperphosphatasemia)

Elevated ALP can originate from liver, bone, or other sources. Pattern recognition and correlation with other tests is essential for diagnosis.

Hepatobiliary Causes (Cholestatic Pattern)

  • Bile duct obstruction: Gallstones, pancreatic cancer, cholangiocarcinoma (ALP often >4x normal)
  • Primary biliary cholangitis (PBC): Autoimmune destruction of intrahepatic bile ducts, anti-mitochondrial antibodies positive
  • Primary sclerosing cholangitis (PSC): Fibrosing cholangitis often associated with inflammatory bowel disease
  • Drug-induced cholestasis: Anabolic steroids, phenothiazines, oral contraceptives, antibiotics
  • Infiltrative liver disease: Sarcoidosis, amyloidosis, lymphoma, metastatic cancer
  • Sepsis: Cholestasis of sepsis can cause isolated ALP elevation
  • Total parenteral nutrition (TPN): Can cause cholestatic liver injury

Bone Causes

  • Paget's disease of bone: Can cause ALP >1000 IU/L, localized bone pain and deformity
  • Bone metastases: Especially osteoblastic metastases (prostate, breast cancer)
  • Healing fractures: Peak ALP at 4-6 weeks post-fracture
  • Osteomalacia/Rickets: Vitamin D deficiency causing impaired bone mineralization
  • Hyperparathyroidism: Increased bone turnover from elevated PTH
  • Renal osteodystrophy: Chronic kidney disease causing bone disease

Physiologic Elevations

  • Childhood and adolescence: Bone growth causes 2-3x normal levels
  • Pregnancy (3rd trimester): Placental ALP production, up to 2-3x baseline
  • Post-prandial (after meals): Intestinal ALP, especially in blood types O and B

Other Causes

  • Chronic kidney disease: Renal osteodystrophy and bone disease
  • Hyperthyroidism: Increased bone turnover
  • Congestive heart failure: Hepatic congestion can elevate ALP
  • Malignancy: Some tumors produce ectopic ALP (Regan isoenzyme)

Decreased ALP (Hypophosphatasemia)

Low ALP is less common and clinically less significant than elevated levels.

Causes of Low ALP

  • Hypophosphatasia: Rare genetic disorder with deficient ALP activity, causes rickets-like bone disease
  • Hypothyroidism: Decreased metabolic activity and bone turnover
  • Zinc deficiency: Zinc is a cofactor for ALP
  • Malnutrition: Severe protein-calorie malnutrition
  • Vitamin C deficiency (scurvy): Impaired osteoblast function
  • Pernicious anemia: B12 deficiency can lower ALP
  • Medications: Excessive vitamin D intake, clofibrate
Interpretation Guidelines

Pattern Recognition: Hepatocellular vs Cholestatic Injury

The R-value helps classify liver injury patterns and guide differential diagnosis. This calculation uses the ratio of ALT to ALP elevations.

R-Value Calculation
R-value = (ALT / ULNALT) ÷ (ALP / ULNALP)

Where ULN = Upper Limit of Normal for each test. The R-value classifies the pattern of liver injury.

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R-Value Pattern Typical Causes
R ≥ 5 Hepatocellular Viral hepatitis, ischemic hepatitis, drug-induced hepatitis, autoimmune hepatitis
R = 2-5 Mixed Chronic hepatitis, cirrhosis, nonalcoholic steatohepatitis (NASH)
R < 2 Cholestatic Bile duct obstruction, PBC, PSC, drug-induced cholestasis, infiltrative disease

Differentiating Liver from Bone Source

When ALP is elevated in isolation, determining the source is critical for diagnosis and management.

Step-by-Step Approach to Elevated ALP

  1. Check GGT or 5'-nucleotidase:
    • If GGT/5'-NT is elevated → Hepatobiliary source likely
    • If GGT/5'-NT is normal → Bone or other source likely
  2. Review other liver tests:
    • If bilirubin, ALT, AST are elevated → Liver disease confirmed
    • If all other LFTs normal → Consider bone source, imaging, or physiologic causes
  3. Consider patient age and context:
    • Children/adolescents → Likely physiologic from bone growth
    • Pregnant (3rd trimester) → Likely placental isoenzyme
    • Elderly with bone pain → Consider Paget's disease, metastases
  4. Consider imaging if hepatobiliary source:
    • Right upper quadrant ultrasound for bile duct dilation
    • MRCP or ERCP for detailed biliary tree evaluation
    • CT abdomen for masses, infiltration
  5. Consider bone imaging if bone source:
    • X-rays of symptomatic areas
    • Bone scan for metastases or Paget's disease
    • Bone-specific ALP if available

Magnitude of Elevation

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ALP Level Degree of Elevation Common Causes
1-2x ULN Mild elevation Fatty liver, medications, mild cholestasis, physiologic (pregnancy, growth)
2-5x ULN Moderate elevation Cholestatic liver disease, infiltrative disease, bone disease
>5x ULN Severe elevation Bile duct obstruction, PBC, PSC, Paget's disease, bone metastases
>10x ULN Marked elevation Complete bile duct obstruction, Paget's disease (can reach >1000 IU/L)
Interfering Factors

Factors That Increase ALP

  • Medications (Cholestatic): Anabolic steroids, oral contraceptives, phenothiazines (chlorpromazine), erythromycin, azithromycin, sulfonamides, allopurinol, captopril
  • Medications (Bone): Anticonvulsants (phenytoin, carbamazepine), aluminum-containing antacids
  • Age factors: Children and adolescents (bone growth), elderly (increased bone turnover)
  • Pregnancy: Especially 3rd trimester due to placental isoenzyme production
  • Blood type O and B: Intestinal ALP elevation after fatty meals (typically mild)
  • Healing fractures: Peaks at 4-6 weeks post-injury
  • Recent surgery: Bone trauma or manipulation
  • Vigorous exercise: Can cause transient mild elevation

Factors That Decrease ALP

  • Medications: Vitamin D excess, clofibrate, zinc supplementation
  • Hypothyroidism: Decreased metabolic activity
  • Nutritional deficiencies: Zinc deficiency, vitamin C deficiency (scurvy), severe malnutrition
  • Sample handling: Prolonged storage at room temperature can decrease ALP

Assay Variations

Different laboratory methods may produce different results:

  • Temperature of assay (30°C vs 37°C) affects reference ranges
  • Method variations between laboratories can differ by 10-20%
  • Always use the reference range provided by the performing laboratory
  • Serial measurements should ideally be performed at the same laboratory

Pre-analytical Factors

  • Hemolysis: Can falsely decrease ALP
  • Lipemia: May interfere with some assay methods
  • Recent meals: Intestinal ALP can increase after fatty meals in blood types O and B
  • Time of day: ALP shows minimal diurnal variation but is slightly higher in afternoon
Clinical Pearls
  • "GGT follows ALP to the liver": If ALP is elevated, order GGT or 5'-nucleotidase to confirm hepatic source. If GGT is also elevated, the ALP is coming from the liver. If GGT is normal, think bone or other sources.
  • Rule of 2s for ALP in pregnancy: ALP can be up to 2-3 times normal in the 3rd trimester due to placental production. This is physiologic and requires no intervention unless other LFTs are abnormal or patient is symptomatic.
  • Paget's disease can have ALP >1000 IU/L: Extremely high ALP levels (>1000) in elderly patients with bone pain suggest Paget's disease. Other LFTs should be normal, and bone-specific imaging shows characteristic findings.
  • The "lonely ALP" in children is normal: An isolated ALP elevation in a healthy child or adolescent without other abnormal LFTs is almost always due to bone growth. No further workup is needed unless symptoms suggest liver or bone disease.
  • Don't forget post-prandial ALP: Patients with blood type O or B can have mild ALP elevations (usually <1.5x normal) after eating fatty meals due to intestinal isoenzyme release. This is benign.
  • R-value guides your differential: Calculate the R-value (ALT/ALP ratio) to classify liver injury as hepatocellular (R≥5), mixed (R=2-5), or cholestatic (R<2). This narrows your differential dramatically.
  • Cholestatic pattern = think obstruction first: When you see ALP >3-4x normal with high bilirubin and low R-value, your first thought should be bile duct obstruction. Order an ultrasound to look for ductal dilation.
  • AST:ALT ratio >2 plus elevated GGT = alcohol: When evaluating elevated ALP with cholestatic pattern, check AST:ALT ratio. If >2:1 with elevated GGT, suspect alcohol-related liver disease.
  • Always correlate ALP with age: A "normal" adult ALP (100 IU/L) in a growing child might actually be inappropriately low and could indicate hypophosphatasia or malnutrition. A "high" ALP (250 IU/L) in an adolescent is completely normal.
  • Serial ALP trends matter more than single values: Rising ALP in a patient with known liver disease suggests worsening cholestasis or new obstruction. Falling ALP after relief of obstruction confirms therapeutic success.
  • When ALP and bilirubin don't match, think early: ALP rises earlier than bilirubin in bile duct obstruction. If you see isolated ALP elevation with normal bilirubin in a symptomatic patient, don't ignore it - partial or early obstruction is possible.
  • Infiltrative disease loves ALP: Granulomatous diseases (sarcoidosis, TB), malignancy (lymphoma, metastases), and amyloidosis preferentially elevate ALP often with minimal transaminase elevation. Consider imaging and possibly liver biopsy.
  • Don't forget medication review: Many commonly prescribed drugs cause cholestatic liver injury with ALP elevation: antibiotics (especially azithromycin, amoxicillin-clavulanate), anabolic steroids, oral contraceptives, phenothiazines. Check medication list first.
  • Normal ALP essentially rules out significant cholestasis: If you're considering bile duct obstruction or cholestatic liver disease and the ALP is normal, you're likely wrong. Cholestasis almost always elevates ALP.
  • Use imaging wisely: Right upper quadrant ultrasound is the first-line imaging for suspected cholestasis - it's cheap, safe, and excellent for detecting bile duct dilation. Save MRCP/ERCP for when you need detailed biliary anatomy or therapeutic intervention.
References
  1. Kratz, A., Ferraro, M., Sluss, P. M., & Lewandrowski, K. B. (2004). Laboratory reference values. New England Journal of Medicine, 351, 1548-1564.
  2. Lee, M. (Ed.). (2009). Basic skills in interpreting laboratory data. Ashp.
  3. Farinde, A. (2021). Lab values, normal adult: Laboratory reference ranges in healthy adults. Medscape. https://emedicine.medscape.com/article/2172316-overview?form=fpf
  4. Nickson, C. (n.d.). Critical Care Compendium. Life in the Fast Lane • LITFL. https://litfl.com/ccc-critical-care-compendium/
  5. Farkas, Josh MD. (2015). Table of Contents - EMCrit Project. EMCrit Project. https://emcrit.org/ibcc/toc/
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