What is the workup for a patient with elevated alkaline phosphatase (ALP)?

Workup for Elevated Alkaline Phosphatase

Begin by measuring gamma-glutamyl transferase (GGT) or 5'-nucleotidase concurrently with ALP to determine whether the elevation originates from hepatobiliary or bone sources. 1

Initial Diagnostic Steps

Confirm the Source of Elevation

• Measure GGT: Elevated GGT confirms hepatobiliary origin, while normal GGT suggests bone or other non-hepatic sources 1
• Alternative confirmation: If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone 1
• 5'-nucleotidase: Elevations generally signal hepatobiliary disease and can serve as an alternative confirmatory test 1

Classify Severity to Guide Urgency

• Mild elevation: <5 times upper limit of normal (ULN) 1
• Moderate elevation: 5-10 times ULN 1
• Severe elevation: >10 times ULN—requires expedited workup due to high association with serious pathology including sepsis, malignant obstruction, and AIDS 1, 2

Hepatobiliary Workup (if GGT elevated)

Medication and History Review

• Comprehensive medication review: Particularly critical in older patients, as cholestatic drug-induced liver injury comprises up to 61% of cases in patients ≥60 years 1
• Alcohol intake screening: >20 g/day in women, >30 g/day in men 1
• Assess for symptoms: Right upper quadrant pain, fatigue, nausea, weight loss, jaundice 1
• Review for parenteral nutrition: Can cause ALP elevation through chronic cholestasis, with incidence up to 65% in home parenteral nutrition patients 1

First-Line Imaging

• Abdominal ultrasound: First-line imaging to evaluate for dilated intrahepatic or extrahepatic ducts, gallstones, infiltrative liver lesions, or masses 1
• Direct to ERCP: If common bile duct stones are demonstrated on ultrasound 1

Second-Line Imaging (if ultrasound negative but ALP remains elevated)

• MRI with MRCP: Superior for detecting intrahepatic biliary abnormalities, primary sclerosing cholangitis, and subtle biliary obstruction 1
• High-quality MRC: Specifically recommended for patients with inflammatory bowel disease and suspected primary sclerosing cholangitis 1

Additional Laboratory Tests

• Viral hepatitis serologies (HAV, HBV, HCV) if risk factors present 1
• Autoimmune markers: ANA, ASMA, and IgG levels if autoimmune overlap syndrome suspected 1
• Fractionated bilirubin: Determine percentage of direct bilirubin to help differentiate causes 1

Key Hepatobiliary Differential Diagnoses

• Cholestatic liver diseases: Primary biliary cholangitis, primary sclerosing cholangitis, drug-induced cholestasis 1
• Biliary obstruction: Choledocholithiasis (18% of adults undergoing cholecystectomy have this), malignant obstruction, biliary strictures 1
• Infiltrative diseases: Hepatic metastases (most common cause in one study at 57%), amyloidosis, sarcoidosis 1, 3
• Sepsis: Can cause extremely high ALP (>1,000 U/L) often with normal bilirubin 2
• Other: Cirrhosis, chronic hepatitis, congestive heart failure 1

When to Consider Liver Biopsy

• Small-duct PSC: When high-quality MRCP is normal in patients with IBD and suspected PSC 1
• Unclear diagnosis: After comprehensive imaging fails to establish etiology 1

Bone Workup (if GGT normal)

Clinical Assessment

• Bone pain or localized symptoms: Indicates need for targeted imaging 4
• Age considerations: Physiologically higher in childhood due to bone growth; patients under 40 with suspected bone pathology may require urgent referral to bone sarcoma center 1
• Postmenopausal women: Bone scan recommended only if elevated ALP accompanied by bone pain or radiographic findings 1

Imaging Studies

• Bone scan: Indicated for localized bone pain or elevated ALP suggesting bone origin 4
• Targeted imaging: Based on symptoms for suspected malignancy 1

Bone-Specific Laboratory Tests

• Bone-specific ALP (B-ALP): Sensitive marker for bone turnover and bone metastases, though less useful when liver ALP is also elevated 1
• Note medication effects: Bisphosphonates and denosumab can alter ALP levels despite underlying pathology 1

Key Bone Differential Diagnoses

• Paget's disease of bone 1
• Bony metastases: Second most common cause in one study at 29% 3
• Fractures 1
• Physiologic causes: Childhood growth, pregnancy (placental production) 1

Follow-Up Strategy

If Initial Evaluation Unrevealing

• Repeat ALP measurement: In 1-3 months 1, 5
• Monitor closely: If ALP continues to rise, as this may indicate progression of underlying disease 1
• Natural history: In hospitalized patients, 52% of isolated ALP elevations normalize within 1-3 months, particularly if initial elevation <1.5 times normal 5

Prognostic Considerations

• Persistent elevation: Usually associated with clinically obvious diagnosis, often life-threatening in hospitalized patients 5
• Mortality: In one study, 47% of patients with isolated elevated ALP of unclear etiology died within average of 58 months, predominantly those with underlying malignancy 3
• Higher initial values: If initial ALP >1.5 times normal, higher likelihood of persistent elevation (68% vs 41%) 5

Critical Pitfalls to Avoid

• Do not attribute to NASH: Elevation of ALP ≥2× ULN is atypical in non-alcoholic steatohepatitis 1
• Do not miss Wilson disease: In acute liver failure with markedly subnormal ALP (<40 IU/L), Coombs-negative hemolytic anemia, and ALP/total bilirubin ratio <2, strongly suspect Wilson disease 6
• Do not overlook sepsis: Can cause extremely high ALP with normal bilirubin, particularly in immunocompromised patients 2
• Do not ignore malignancy: Most common cause of isolated elevated ALP in one study (57%), particularly infiltrative intrahepatic malignancy 3