What is the further workup for a patient with elevated alkaline phosphatase (alk phos)?

Further Workup for Elevated Alkaline Phosphatase

Initial Step: Confirm Hepatic vs. Bone Origin

Measure gamma-glutamyl transferase (GGT) immediately to determine the tissue source of elevated ALP. 1 GGT is found in liver, kidneys, intestine, prostate, and pancreas but critically is NOT found in bone, making it the key discriminator between hepatobiliary and bone etiologies. 2

• If GGT is elevated: The ALP is hepatic in origin—proceed to hepatobiliary workup below 1
• If GGT is normal: The ALP is likely from bone—proceed to bone workup below 1
• Alternatively, obtain ALP isoenzyme fractionation if GGT is unavailable or equivocal to determine the percentage derived from liver versus bone 1, 3

Hepatobiliary Workup (When GGT is Elevated)

Complete Laboratory Panel

Obtain the following tests to characterize the pattern and severity of liver injury:

• Complete liver panel: ALT, AST, total and direct bilirubin, albumin 1
• Calculate the R value: (ALT/ULN)/(ALP/ULN) to classify injury pattern—cholestatic (R ≤2), mixed (R >2 and <5), or hepatocellular (R ≥5) 1
• Fractionated bilirubin: Determine the percentage of direct bilirubin, as elevations suggest more advanced biliary obstruction or hepatocellular dysfunction 1

Severity Classification Guides Urgency

• Mild elevation: <5× upper limit of normal (ULN) 1
• Moderate elevation: 5-10× ULN—expedite workup with imaging and laboratory evaluation 1
• Severe elevation: >10× ULN—requires expedited workup given high association with serious pathology including malignancy, sepsis, and biliary obstruction 1, 4, 5

First-Line Imaging: Abdominal Ultrasound

Perform transabdominal ultrasound as the first-line imaging modality to assess for dilated intra- or extrahepatic ducts, gallstones, infiltrative liver lesions, or masses. 1, 2

• If ultrasound shows common bile duct stones: Proceed directly to ERCP for both diagnosis and therapeutic intervention without further imaging 1, 2
• If ultrasound shows biliary ductal dilatation: Proceed to MRI with MRCP to determine the cause of obstruction 2
• 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, small duct disease, and partial bile duct obstruction 1, 2

Additional Testing Based on Clinical Context

• Autoimmune markers: Check ANA, ASMA, AMA, and IgG levels if autoimmune liver disease is suspected 1
• Viral hepatitis serologies: HAV IgM, HBsAg, HBc IgM, and HCV antibody if risk factors are present 1, 2
• Medication review: Critical in older patients, as cholestatic drug-induced liver injury comprises up to 61% of cases in patients ≥60 years 1

Special Considerations for Inflammatory Bowel Disease

If the patient has inflammatory bowel disease and elevated ALP, obtain high-quality MRCP to evaluate for primary sclerosing cholangitis. 1, 3 If MRCP is normal but PSC is still suspected, consider liver biopsy to diagnose small-duct PSC. 1

Bone Workup (When GGT is Normal)

Laboratory Evaluation

• Serum calcium, phosphate, and PTH: To evaluate for metabolic bone disorders 3
• 25-hydroxyvitamin D: To assess for vitamin D deficiency 3
• Bone-specific alkaline phosphatase (B-ALP): To confirm bone origin and assess for bone turnover abnormalities 3, 2

Imaging Strategy

Bone scan is indicated only if the patient has localized bone pain, constitutional symptoms, history of malignancy, or clinical suspicion of bone metastases. 1, 3 Do NOT order bone scan in asymptomatic patients with mildly elevated ALP and normal GGT. 1

• In patients with known malignancy (renal, breast, bladder, prostate), elevated ALP should prompt evaluation for metastatic disease even if asymptomatic 3, 2
• Patients under 40 years with suspected bone pathology and elevated ALP may require urgent referral to a bone sarcoma center 1

Critical Differential Diagnoses by Severity

Extremely High ALP (>1000 U/L)

The most common causes in hospitalized patients are: 4, 5

• Sepsis: Can present with extremely high ALP and normal bilirubin in 70% of cases 4
• Malignant biliary obstruction: Cholangiocarcinoma, pancreatic cancer, metastatic disease 4, 5
• Infiltrative malignancy: In one study, 57% of patients with isolated elevated ALP of unclear etiology had underlying malignancy (intrahepatic metastases, bone metastases, or both) 6

Moderate ALP Elevation

• Choledocholithiasis: Approximately 18% of adults undergoing cholecystectomy have common bile duct stones 1
• Primary biliary cholangitis: Typically presents with ALP 2-10× ULN and positive antimitochondrial antibody 1
• Primary sclerosing cholangitis: ALP typically ≥1.5× ULN, strongly associated with inflammatory bowel disease 1
• Drug-induced cholestasis: Review all medications, particularly in older patients 1, 2

Mild ALP Elevation

• Non-alcoholic fatty liver disease: However, ALP elevation ≥2× ULN is atypical in NASH—do not assume NASH is the cause 1
• Infiltrative non-malignant diseases: Sarcoidosis, amyloidosis 1
• Chronic hepatitis and cirrhosis: Can cause mild ALP elevation 1

Follow-Up Strategy

If initial evaluation is unrevealing, repeat ALP measurement in 1-3 months and monitor closely if ALP continues to rise, as this may indicate progression of underlying disease. 1 Persistent elevation warrants further investigation with advanced imaging (MRI/MRCP) or consideration of liver biopsy if diagnosis remains unclear. 1

Common Pitfalls to Avoid

• Do not assume elevated ALP in infants with parenteral nutrition is due to liver disease: Elevation is predominantly bone-specific ALP reflecting metabolic bone disease, not hepatobiliary pathology 7
• Do not delay ERCP when common bile duct stones are identified on ultrasound: Proceed directly to therapeutic intervention 1, 2
• Do not underestimate the significance of isolated elevated ALP: In one study, 47% of patients with isolated elevated ALP of unclear etiology died within an average of 58 months, predominantly from malignancy 6
• Normal CT does not exclude intrahepatic cholestasis: MRI/MRCP is more sensitive for biliary tree evaluation 1
• Do not assume elevated transaminases exclude biliary obstruction: In acute choledocholithiasis, ALT can surpass ALP, mimicking acute hepatitis 1