What are the differential diagnoses for a patient with palpable right iliac‑fossa lymph nodes and an isolated elevation of total bilirubin?

Differential Diagnoses for Right Iliac Fossa Lymphadenopathy with Elevated Total Bilirubin

The combination of right iliac fossa lymph nodes and raised total bilirubin most likely represents either lymphoma with hepatic involvement, metastatic malignancy (particularly gastrointestinal or gynecologic), or infectious/inflammatory conditions affecting both the abdomen and liver. 1, 2

Immediate Diagnostic Steps

Order fractionated bilirubin (direct and indirect) immediately to determine whether hyperbilirubinemia is conjugated or unconjugated, as this fundamentally directs the diagnostic approach. 3, 4

• If conjugated bilirubin is <20-30% of total, consider Gilbert's syndrome, hemolysis, or medication effects 3, 5
• If conjugated bilirubin is >35% of total, suspect hepatobiliary pathology requiring urgent evaluation 3, 4

Obtain comprehensive liver function tests (ALT, AST, alkaline phosphatase, GGT, albumin, INR/PT) to differentiate hepatocellular injury from cholestatic patterns and assess synthetic function. 3

Primary Differential Diagnoses

Malignant Causes (Most Concerning)

Non-Hodgkin's lymphoma is a critical consideration, as periportal and iliac lymphadenopathy can occur with hepatic infiltration causing conjugated hyperbilirubinemia. 2 In a study of enlarged periportal lymph nodes without identifiable pancreatobiliary cancer, 7 of 64 patients (11%) had non-Hodgkin's lymphoma. 2

Metastatic carcinoma from gastrointestinal (appendiceal, cecal, colon), gynecologic (ovarian, cervical), or genitourinary primaries can present with right iliac fossa lymphadenopathy and liver involvement. 2 Five of 64 patients (8%) with enlarged periportal nodes had metastatic carcinoma. 2

Hepatobiliary malignancies (cholangiocarcinoma, gallbladder carcinoma, hepatocellular carcinoma) can cause both periportal lymphadenopathy and obstructive jaundice. 6, 2

Infectious/Inflammatory Causes

Granulomatous disease (tuberculosis, sarcoidosis) can cause both abdominal lymphadenopathy and hepatic granulomas with cholestatic liver injury. 2 Four patients in the periportal lymphadenopathy series had granulomas on fine-needle aspiration. 2

Cholangitis with reactive lymphadenopathy presents with conjugated hyperbilirubinemia, fever, right upper quadrant pain (Charcot's triad), and can have associated mesenteric/iliac lymph nodes. 6, 3

Lipogranulomatosis was found in 8 of 64 patients with enlarged periportal nodes, representing a benign inflammatory process. 2

Benign Causes

Gilbert's syndrome with coincidental benign lymphadenopathy should be considered if unconjugated bilirubin comprises >70-80% of total bilirubin with normal liver enzymes. 3, 5 However, palpable iliac nodes are abnormal and require investigation regardless. 1

Appendicitis or cecal pathology can cause right iliac fossa lymphadenopathy; if complicated by sepsis, this can produce conjugated hyperbilirubinemia. 6, 7

Diagnostic Algorithm

Step 1: Laboratory Evaluation (Within 24 Hours)

• Fractionated bilirubin to determine conjugated vs. unconjugated 3, 4
• Complete liver panel (ALT, AST, alkaline phosphatase, GGT, albumin, INR/PT) 3
• Complete blood count with differential and peripheral smear to evaluate for hemolysis, lymphocytosis, or cytopenias suggesting marrow involvement 3, 1
• Lactate dehydrogenase (elevated in lymphoma and hemolysis) 3
• Inflammatory markers (ESR, CRP) to assess for infection or inflammation 1

Step 2: Imaging (Within 24-48 Hours)

Obtain abdominal ultrasound immediately as first-line imaging, which has 98% positive predictive value for liver parenchymal disease and 65-95% sensitivity for biliary obstruction. 3, 7 Ultrasound will evaluate:

• Liver parenchyma for masses, infiltration, or cirrhosis 3
• Biliary tree for dilation or obstruction 6, 3
• Right iliac fossa mass characteristics (solid vs. cystic, vascular flow) 7
• Additional lymphadenopathy (periportal, celiac, mesenteric) 2

If ultrasound shows biliary dilation or clinical suspicion remains high, proceed to CT abdomen/pelvis with IV contrast to:

• Stage potential malignancy 6
• Identify lymphadenopathy distribution (iliac, retroperitoneal, mesenteric) 1, 2
• Detect primary tumor sites 2

Consider MRI with MRCP if primary sclerosing cholangitis or cholangiocarcinoma is suspected based on cholestatic pattern with biliary dilation. 6, 3

Step 3: Tissue Diagnosis

Palpable iliac nodes are abnormal and warrant tissue sampling, especially when combined with unexplained hyperbilirubinemia. 1

• EUS-guided fine-needle aspiration is recommended for periportal or peripancreatic nodes, with diagnostic yield in 97% of cases for identifying organ of origin. 2
• Image-guided core needle biopsy of iliac nodes provides better tissue architecture than fine-needle aspiration for lymphoma diagnosis 1
• Excisional biopsy may be necessary if fine-needle aspiration is non-diagnostic and clinical suspicion for lymphoma remains high 1

Critical Clinical Pitfalls

Do not assume isolated unconjugated hyperbilirubinemia is benign Gilbert's syndrome without excluding hemolysis (reticulocyte count, haptoglobin, LDH, peripheral smear). 3, 5

Do not attribute palpable iliac lymph nodes to reactive changes without tissue diagnosis, as 18.8% of enlarged periportal nodes without obvious pancreatobiliary cancer harbor malignancy. 2

Do not delay imaging for conjugated hyperbilirubinemia, as biliary obstruction requires intervention within 24-48 hours to prevent cholangitis and hepatic decompensation. 6, 3

Verify that elevated alkaline phosphatase is of hepatic origin by measuring GGT, as bone metastases can cause isolated alkaline phosphatase elevation without liver involvement. 6, 3

In patients with cholestatic disease, check INR and vitamin K status before attributing prolonged INR to liver dysfunction, as fat-soluble vitamin deficiencies are correctable with supplementation. 3

Monitoring Strategy

If initial workup shows conjugated hyperbilirubinemia with total bilirubin ≥2× baseline, repeat liver function tests within 7-10 days to assess trend. 3

For unexplained lymphadenopathy >1 cm persisting beyond 4-6 weeks despite conservative management, tissue diagnosis is mandatory. 1, 8

If malignancy is confirmed, staging with PET-CT and bone marrow biopsy (for lymphoma) should be completed within 1-2 weeks. 1