What is the workup for elevated alkaline phosphatase (alk phos) in primary care?

Workup for Elevated Alkaline Phosphatase in Primary Care

Begin by measuring GGT or 5'-nucleotidase to confirm hepatobiliary origin; if elevated, obtain abdominal ultrasound as first-line imaging, while normal GGT suggests bone source requiring bone-specific ALP or targeted bone evaluation. 1, 2

Initial Laboratory Assessment

Confirm the source of ALP elevation first:

• Measure GGT concurrently with ALP—elevated GGT confirms hepatobiliary origin, while normal GGT points to bone or other non-hepatic sources 1, 2
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage from liver versus bone 1
• Alternatively, measure 5'-nucleotidase, as elevations generally signal hepatobiliary disease 2

Obtain a complete liver panel including ALT, AST, total and direct bilirubin, and albumin to assess hepatic function and injury pattern 1, 2

Calculate the R value [(ALT/ULN)/(ALP/ULN)] to classify injury pattern: cholestatic (R ≤2), mixed (R >2 and <5), or hepatocellular (R ≥5) 2

Severity Stratification Guides Urgency

• Mild elevation (<5× ULN): Standard workup with repeat testing in 1-3 months if initial evaluation unrevealing 1, 2
• Moderate elevation (5-10× ULN): Expedite workup with imaging and laboratory evaluation 1, 2
• Severe elevation (>10× ULN): Requires urgent workup given high association with serious pathology including malignancy, sepsis, or biliary obstruction 1, 3

Hepatobiliary Source Workup

When GGT is elevated (hepatic origin confirmed):

First-line imaging is abdominal ultrasound to evaluate for:

• Dilated intrahepatic or extrahepatic bile ducts 1, 2
• Gallstones or choledocholithiasis (present in ~18% of adults with gallbladder disease) 2
• Infiltrative liver lesions or masses 2

If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP, which is superior to CT for detecting:

• Intrahepatic biliary abnormalities 1, 2
• Primary sclerosing cholangitis 1, 2
• Small duct disease 2
• Choledocholithiasis and biliary strictures 2

Additional laboratory tests to consider:

• Medication review is critical, especially in patients >60 years where cholestatic drug-induced liver injury comprises up to 61% of cases 1, 2
• Autoimmune markers (ANA, ASMA, AMA, IgG) if autoimmune liver disease suspected 1, 2
• Viral hepatitis serologies (HAV IgM, HBsAg, HBc IgM, HCV antibody) if risk factors present 2
• Alcohol intake screening (>20 g/day in women, >30 g/day in men) 2

Special consideration for IBD patients: Elevated ALP should raise suspicion for primary sclerosing cholangitis—obtain high-quality MRCP, and if normal, consider liver biopsy for small-duct PSC 2

Bone Source Workup

When GGT is normal (bone origin suspected):

Measure bone-specific alkaline phosphatase (B-ALP) to confirm bone origin 1

Obtain additional bone markers:

• Serum calcium, phosphate, and PTH to evaluate for metabolic bone disorders 1
• 25-hydroxyvitamin D to assess for vitamin D deficiency 1

Imaging recommendations:

• Bone scan is the primary imaging modality if B-ALP is elevated or bone pain is present 1, 2
• Bone scan is particularly indicated for patients with known malignancy (renal, breast, bladder, prostate) who present with elevated ALP or bone pain 1
• Targeted imaging based on localized symptoms (e.g., plain radiographs of symptomatic areas) 2

Urgent referral: Patients under 40 years with suspected bone pathology and elevated ALP may require urgent referral to a bone sarcoma center 2

Critical Differential Diagnoses by Clinical Context

Malignancy is the most common cause in recent observational data:

• 57% of isolated elevated ALP cases were due to underlying malignancy (infiltrative intrahepatic malignancy, bony metastasis, or both) 4
• Extremely high elevations (>1,000 U/L) are most frequently seen with sepsis, malignant biliary obstruction, and AIDS 3

Other important causes to consider:

• Sepsis can cause extremely high ALP with normal bilirubin 3
• Bone disease (Paget's disease, fractures, metastases) accounts for 29% of cases 4
• Infiltrative diseases (sarcoidosis, amyloidosis) 2
• Chronic liver disease (cirrhosis, chronic hepatitis) 2
• Congestive heart failure 2

Follow-Up Strategy

If initial evaluation is unrevealing:

• Repeat ALP measurement in 1-3 months 1, 2
• Monitor closely if ALP continues to rise, as this may indicate progression of underlying disease 1
• In hospitalized patients, 52% of isolated ALP elevations normalize within 1-3 months, often associated with reversible conditions like congestive heart failure 5

Persistent elevation warrants further investigation, as it is usually associated with a clinically significant diagnosis, particularly malignancy (47% mortality within 58 months in one cohort) 4

Common Pitfalls to Avoid

• Do not attribute isolated ALP elevation ≥2× ULN to NASH, as this is atypical for non-alcoholic steatohepatitis 1
• Normal CT does not exclude intrahepatic cholestasis—MRI/MRCP is more sensitive for biliary tree evaluation 2
• Physiologic elevations occur in childhood (bone growth) and pregnancy (placental production) 2
• Treatments like bisphosphonates and denosumab can alter ALP levels despite underlying pathology 2