What are the next steps for a 61-year-old male with thrombocytopenia (platelet count of 131), macrocytosis (MCV of 95), and elevated bilirubin (40)?

Immediate Workup for Suspected Cholestatic Liver Disease with Thrombocytopenia

This patient requires urgent evaluation for cholestatic liver disease, with abdominal ultrasound as the immediate next step, followed by complete fractionated bilirubin, liver enzyme panel, and assessment for hemolysis. 1

Initial Laboratory Assessment

The constellation of mild thrombocytopenia (131 × 10⁹/L), normal-high MCV (95 fL), and markedly elevated bilirubin (40 mg/dL) demands immediate clarification of the bilirubin type:

• Obtain fractionated bilirubin immediately to determine if this is conjugated (direct) or unconjugated (indirect) hyperbilirubinemia, as this fundamentally changes the diagnostic approach 1, 2
• Complete liver enzyme panel including ALT, AST, alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT) to identify hepatocellular versus cholestatic patterns 3, 1
• Check for hemolysis markers: LDH, haptoglobin, reticulocyte count, and direct Coombs test to exclude hemolytic causes given the thrombocytopenia 3
• Coagulation screen including PT/INR and fibrinogen to assess synthetic liver function 3
• Serum albumin as another marker of hepatic synthetic function 3

Critical Imaging

Abdominal ultrasound is the mandatory first-line imaging study with 98% positive predictive value for liver parenchymal disease and 65-95% sensitivity for detecting biliary obstruction 1. This non-invasive, readily available test will:

• Differentiate intrahepatic from extrahepatic cholestasis 3, 1
• Identify bile duct dilation (common bile duct >10mm suggests obstruction) 1
• Detect liver parenchymal changes, masses, or cirrhotic morphology 3
• Assess for portal vein thrombosis or splenomegaly 3

Algorithmic Approach Based on Bilirubin Fractionation

If Predominantly Conjugated (Direct) Hyperbilirubinemia:

This bilirubin level (40 mg/dL) with conjugated predominance indicates severe cholestasis or hepatocellular dysfunction 3, 1:

• If bile duct dilation present on ultrasound: Proceed to MRCP (preferred) or ERCP to identify the site and cause of obstruction 3, 1
• If no bile duct dilation: Consider MRI/MRCP to exclude pathology missed by ultrasound, or MDCT with contrast if MRI contraindicated 1
• Test for antimitochondrial antibodies (AMA) to evaluate for primary biliary cholangitis, especially given the age and presentation 3
• Viral hepatitis serologies (hepatitis A, B, C, E) as acute viral hepatitis can present with marked hyperbilirubinemia 4

If Predominantly Unconjugated (Indirect) Hyperbilirubinemia:

This would suggest hemolysis or impaired conjugation 2:

• Peripheral blood smear to look for schistocytes (microangiopathic hemolysis) given the thrombocytopenia 3
• ADAMTS13 activity if thrombocytopenia is more severe or if there are signs of thrombotic microangiopathy 3
• However, unconjugated bilirubin of 40 mg/dL would be extremely unusual without overt hemolysis 5, 2

Addressing the Thrombocytopenia

The platelet count of 131 × 10⁹/L is mildly reduced and requires contextualization:

• In chronic liver disease, thrombocytopenia commonly results from portal hypertension with splenic sequestration 3
• Check for signs of portal hypertension: splenomegaly on ultrasound, presence of varices 3
• Rule out thrombotic microangiopathy (TMA) if there are additional features: check for schistocytes, elevated LDH, low haptoglobin, and renal dysfunction 3
• Consider drug-induced causes: Review all medications and supplements for hepatotoxic or bone marrow suppressive agents 1
• Exclude hemophagocytic syndrome if ferritin is markedly elevated (>10,000 ng/mL), especially with acute hepatitis 4

MCV Interpretation

The MCV of 95 fL is at the upper limit of normal and may indicate:

• Chronic alcohol use when combined with elevated GGT and AST/ALT ratio >2 3
• Vitamin B12 or folate deficiency, though less likely to cause this degree of hyperbilirubinemia 3
• Reticulocytosis from hemolysis, which should be confirmed with reticulocyte count 3

Critical Pitfalls to Avoid

• Do not delay imaging: With bilirubin of 40 mg/dL, biliary obstruction requiring urgent decompression must be excluded immediately 3, 1
• Do not assume Gilbert syndrome: While Gilbert syndrome causes unconjugated hyperbilirubinemia, it never reaches levels of 40 mg/dL 6
• Do not overlook drug-induced liver injury: This is a common cause of severe hyperbilirubinemia and requires detailed medication history including over-the-counter and herbal supplements 1
• Do not perform liver biopsy before imaging: Biopsy should only be considered after imaging excludes biliary obstruction and when the diagnosis remains unclear 3, 1

Urgent Versus Elective Workup

Given the severity of hyperbilirubinemia (40 mg/dL):

• Same-day ultrasound and laboratory evaluation are mandatory 1
• If bile duct obstruction is identified, urgent ERCP may be therapeutic and diagnostic 3
• If acute liver failure is suspected (elevated INR, encephalopathy, rapidly rising bilirubin), immediate hepatology consultation and consideration for transplant evaluation 3