What work‑up and next steps are indicated for a male patient with a rising alkaline phosphatase (~300 IU/L) and a macrocytic anemia (Hgb 12.2 g/dL, Hct 37.3 %, MCV 106.6 fL) with normal vitamin B12, liver transaminases, bilirubin and PSA?

Workup for Rising Alkaline Phosphatase with Macrocytic Anemia

This patient requires immediate imaging with abdominal ultrasound followed by MRCP if unrevealing, plus serologic testing for autoimmune cholestatic disease, because the combination of steadily rising alkaline phosphatase (292 IU/L, >2× ULN) and macrocytic anemia (MCV 106.6 fL, Hgb 12.2 g/dL) with normal B12 suggests either infiltrative liver disease or an autoimmune cholestatic process with concurrent chronic disease anemia. 1

Immediate Diagnostic Steps

Confirm Hepatic Origin of Alkaline Phosphatase

• Order gamma-glutamyl transferase (GGT) immediately to confirm the hepatic source of the elevated alkaline phosphatase, as elevated GGT confirms hepatobiliary origin while normal GGT suggests bone disease. 1
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to quantify the percentage derived from liver versus bone, intestine, or other sources. 1

Imaging Strategy

• Abdominal ultrasound is the mandatory first-line imaging study to assess for dilated intra- or extrahepatic bile ducts, gallstones, infiltrative liver lesions, masses, and hepatosplenomegaly. 1
• If ultrasound is negative but alkaline phosphatase remains elevated, proceed immediately 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

Essential Serologic Workup

• Antimitochondrial antibody (AMA) – positive in primary biliary cholangitis; diagnosis requires elevated ALP plus positive AMA. 1
• Antinuclear antibody (ANA) with sp100/gp210 subtyping – supports PBC variants when AMA is negative. 1
• Anti-smooth muscle antibody (ASMA) and quantitative IgG – to screen for autoimmune hepatitis overlap syndromes, as ALP >2× ULN that fails to normalize suggests AIH/PBC or AIH/PSC overlap. 1
• Viral hepatitis serologies (HAV IgM, HBsAg, HBc IgM, HCV antibody) if risk factors are present. 1

Anemia Evaluation

Macrocytic Anemia Workup

• Although vitamin B12 is normal (338 pg/mL), order serum and red cell folate levels to exclude folate deficiency, as the three most common causes of macrocytosis are B12/folate deficiency, liver disease, and reticulocytosis. 2
• Review the peripheral blood smear for oval macrocytes (suggesting megaloblastic anemia), round macrocytes (suggesting liver disease), or teardrop cells and hypersegmented neutrophils (suggesting B12 deficiency with hemolysis). 2, 3
• Measure reticulocyte count to assess for hemolysis or bone marrow response; in reticulocytosis, MCV rarely exceeds 110 fL. 2
• Check lactate dehydrogenase (LDH) and indirect bilirubin to evaluate for hemolysis, as megaloblastic anemia can present with elevated LDH and indirect hyperbilirubinemia. 3

Anemia of Chronic Disease

• The combination of macrocytic anemia with rising alkaline phosphatase and normal B12 strongly suggests anemia of chronic disease secondary to underlying malignancy, chronic infection, or inflammatory disorders such as sarcoidosis or autoimmune hepatitis. 1
• Complete blood count with differential should be reviewed for leukopenia or thrombocytopenia, which may indicate infiltrative bone marrow disease or hypersplenism from portal hypertension. 1

Differential Diagnosis by Severity

Moderate Elevation (ALP 2–5× ULN, as in this patient at 292 IU/L)

• Primary biliary cholangitis (PBC) – typically presents with ALP 2–10× ULN, positive AMA, and elevated IgG in 61% of patients. 1
• Primary sclerosing cholangitis (PSC) – ALP typically ≥1.5× ULN, strongly associated with inflammatory bowel disease (present in 50–80% of PSC patients); MRCP shows characteristic "beading" of bile ducts. 1
• Infiltrative liver disease – hepatic metastases account for 57% of unexplained isolated ALP elevations in hospitalized adults; also consider sarcoidosis and amyloidosis. 1, 4
• Partial bile duct obstruction – choledocholithiasis, biliary strictures, or malignant obstruction can cause fluctuating ALP and bilirubin levels. 1
• Drug-induced cholestatic liver injury – accounts for up to 61% of cholestatic injury cases in patients ≥60 years; review all medications, supplements, and over-the-counter agents. 1

Macrocytic Anemia with Liver Disease

• In liver disease, macrocytosis is typically mild and uniform, with round RBCs and MCV rarely exceeding 110 fL. 2
• Alcohol-related liver disease should be considered; screen for alcohol intake >20 g/day in women or >30 g/day in men, and note that 75% of regular drinkers exhibit elevated GGT. 1

Critical Next Steps

Immediate Actions

• Order abdominal ultrasound and GGT today to confirm hepatic origin and assess for structural abnormalities. 1
• Order AMA, ANA (with sp100/gp210), ASMA, quantitative IgG, and viral hepatitis serologies concurrently with imaging to avoid diagnostic delay. 1
• Measure serum and red cell folate, reticulocyte count, LDH, and indirect bilirubin to complete the anemia workup. 2, 3

Follow-Up Imaging

• If ultrasound is negative, proceed to MRI with MRCP within 7–10 days, as a normal ultrasound does not exclude intrahepatic cholestasis, PSC, PBC, or infiltrative disease. 1
• MRCP demonstrates 86% sensitivity and 94% specificity for diagnosing PSC and is superior for detecting intrahepatic biliary abnormalities. 1

Monitoring Strategy

• Repeat alkaline phosphatase, transaminases, and bilirubin in 7–10 days to confirm reproducibility and direction of change; rising ALP suggests progressive disease requiring expedited workup. 1
• If ALP continues to rise or exceeds 5× ULN, expedite imaging and consider urgent hepatology referral. 1

Common Pitfalls to Avoid

• Do not assume non-alcoholic steatohepatitis (NASH) is the cause of ALP elevation ≥2× ULN, as NASH typically causes ALT elevation more than ALP. 1
• Do not rely solely on ultrasound; a normal ultrasound does not exclude PSC, PBC, or intrahepatic cholestasis, and MRCP is mandatory if ALP remains elevated. 1
• Do not delay serologic testing while awaiting imaging results; order AMA, ANA, and other autoimmune markers concurrently to avoid diagnostic delay. 1
• Do not overlook drug-induced cholestasis, especially in older patients; review all medications, including over-the-counter agents and supplements. 1
• Do not assume normal B12 excludes all causes of macrocytic anemia; folate deficiency, liver disease, and reticulocytosis must still be evaluated. 2
• Do not ignore the anemia; the combination of rising ALP and macrocytic anemia may indicate infiltrative malignancy, chronic disease, or hemolysis requiring urgent evaluation. 1, 4

Severity-Based Urgency

• This patient's ALP of 292 IU/L (approximately 2× ULN) with macrocytic anemia warrants expedited workup within 1–2 weeks, as the combination suggests infiltrative disease, autoimmune cholestatic disease, or malignancy. 1
• If imaging reveals hepatic metastases, dominant biliary stricture, or mass lesion, urgent hepatology or oncology referral is indicated. 1