In a female patient with mild transaminase elevation, negative anti‑smooth‑muscle antibodies and negative anti‑mitochondrial antibodies, and cervical lymphadenopathy, what is the most appropriate next step in management?

Cervical Lymphadenopathy with Mild Transaminase Elevation and Negative Autoimmune Serology

Obtain an excisional cervical lymph node biopsy immediately to evaluate for Kikuchi disease (histiocytic necrotizing lymphadenitis) or hemophagocytic lymphohistiocytosis (HLH), both of which can present with cervical lymphadenopathy, mild transaminase elevation, and negative autoimmune markers. 1

Diagnostic Rationale

The combination of cervical lymphadenopathy with mild hepatic enzyme elevation and negative anti-smooth muscle and anti-mitochondrial antibodies makes primary autoimmune liver disease unlikely as the primary diagnosis. This clinical constellation instead suggests a systemic inflammatory or lymphoproliferative process affecting both lymph nodes and liver.

Why Autoimmune Hepatitis Is Unlikely

• Anti-smooth muscle antibody (SMA) is present in 63% of autoimmune hepatitis (AIH) patients at presentation, and antinuclear antibody (ANA) is detected in 80% of white North American adults with AIH. 2

• When both conventional antibodies are negative, anti-SLA testing (99% specificity for AIH) and atypical p-ANCA (present in 50-92% of type 1 AIH) should be obtained before excluding AIH. 2

• Cervical lymphadenopathy is not a typical feature of AIH; when lymphadenopathy occurs in autoimmune liver disease, it is usually associated with systemic autoimmune conditions rather than isolated hepatic autoimmunity. 3

Why Primary Biliary Cholangitis Is Unlikely

• Anti-mitochondrial antibody (AMA) is the diagnostic hallmark of primary biliary cholangitis (PBC), detected in >90% of affected individuals with specificity greater than 95%. 4

• The negative AMA essentially excludes PBC as the primary diagnosis, though 5-10% of PBC cases are AMA-negative and instead have PBC-specific antinuclear antibodies (anti-sp100, anti-gp210). 4, 5

• PBC characteristically presents with cholestatic enzyme elevation (alkaline phosphatase and GGT) rather than transaminase elevation, and cervical lymphadenopathy is not a recognized feature. 4

Differential Diagnosis Requiring Urgent Evaluation

Kikuchi Disease (Histiocytic Necrotizing Lymphadenitis)

• A 13-year-old female with fever, seizure, and cervical lymphadenopathy showed pancytopenia and elevation of serum transaminase, lactate dehydrogenase, triglyceride, and ferritin; lymph node biopsy revealed Kikuchi disease with hemophagocytic phenomenon in bone marrow. 1

• Kikuchi disease can present with cervical lymphadenopathy, fever, and mild-to-moderate transaminase elevation; it is more common in young females and typically has a self-limited course. 1

• Lymph node biopsy showing necrotizing lymphadenitis with proliferation of histiocytes is diagnostic. 6

Hemophagocytic Lymphohistiocytosis (HLH)

• HLH can present with fever, cervical lymphadenopathy, hepatosplenomegaly, pancytopenia, elevated transaminases, elevated ferritin (often >500 ng/mL), and elevated triglycerides. 1

• Bone marrow examination showing hemophagocytosis in the setting of fever, splenomegaly, cytopenias, hypertriglyceridemia, and hyperferritinemia establishes the diagnosis. 1

• HLH associated with Kikuchi disease in childhood has a less aggressive clinical course and better prognosis than primary HLH. 1

Chronic Active Epstein-Barr Virus (CAEBV) Infection

• A 19-year-old with fever, fatigue, cervical lymphadenopathy, hepatosplenomegaly, and moderately elevated transaminases had extremely elevated EBV antibody titers (VCA IgG 2560×, EA IgG 1280×); cervical lymph node biopsy showed necrotizing lymphadenitis with histiocyte proliferation. 6

• CAEBV can present with persistent or recurrent fever, lymphadenopathy, hepatosplenomegaly, elevated transaminases, and hemophagocytosis in liver, spleen, and bone marrow. 6

• EBV serology (VCA IgG, VCA IgM, EA IgG, EBNA) should be obtained in patients with this clinical presentation. 6

Recommended Diagnostic Algorithm

Immediate Laboratory Testing

• Complete blood count with differential to assess for cytopenias suggesting HLH or systemic inflammatory process. 1

• Comprehensive metabolic panel including ALT, AST, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and INR to characterize the pattern of liver injury (hepatocellular vs. cholestatic). 3

• Ferritin, triglycerides, and lactate dehydrogenase to screen for HLH (ferritin >500 ng/mL and triglycerides >265 mg/dL support HLH). 1

• EBV serology (VCA IgG, VCA IgM, EA IgG, EBNA) to evaluate for acute or chronic EBV infection. 6

• Hepatitis B surface antigen, hepatitis C antibody with reflex PCR, and anti-hepatitis E IgM to exclude viral hepatitis. 3

Expanded Autoantibody Panel (If Not Already Done)

• Anti-SLA (soluble liver antigen) antibody, which has 99% specificity for AIH and may be the sole marker in 14-20% of AIH cases. 2

• Atypical p-ANCA, which is present in 50-92% of type 1 AIH patients and may be the only positive autoantibody when conventional antibodies are negative. 2

• Anti-LKM1 (liver-kidney microsomal type 1) and anti-LC1 (liver cytosol type 1) to exclude type 2 AIH, which is characterized by these antibodies in the absence of ANA/SMA. 2

• PBC-specific antinuclear antibodies (anti-sp100, anti-gp210) if cholestatic pattern is present, as these have equivalent diagnostic accuracy to AMA in AMA-negative PBC. 4

Imaging

• Abdominal ultrasound with Doppler to evaluate liver morphology, exclude biliary obstruction, assess for hepatosplenomegaly, and look for cirrhotic signs. 3

• Chest radiograph to exclude mediastinal lymphadenopathy or pulmonary involvement. 6

Tissue Diagnosis

• Excisional cervical lymph node biopsy is the definitive diagnostic procedure; it should be performed promptly to evaluate for Kikuchi disease, lymphoma, or other lymphoproliferative disorders. 1, 6

• Bone marrow aspiration and biopsy should be obtained if HLH is suspected based on fever, cytopenias, hyperferritinemia, and hypertriglyceridemia; hemophagocytosis in bone marrow confirms the diagnosis. 1

• Liver biopsy is not indicated as the initial diagnostic procedure in this clinical scenario because the cervical lymphadenopathy suggests a systemic process rather than primary liver disease; however, it may be considered if lymph node biopsy is non-diagnostic and autoimmune liver disease remains in the differential. 3, 2

Management Pending Diagnosis

• Avoid empiric immunosuppression (corticosteroids or other immunosuppressive agents) until tissue diagnosis is established, as this may obscure the diagnosis of lymphoma or infection and worsen outcomes in certain conditions. 3

• If HLH is strongly suspected based on clinical criteria (fever, splenomegaly, cytopenias, hyperferritinemia >500 ng/mL, hypertriglyceridemia >265 mg/dL), urgent hematology consultation is warranted because HLH can be rapidly fatal without prompt treatment. 1

• If Kikuchi disease is confirmed on lymph node biopsy, treatment with intravenous immunoglobulin and corticosteroids may be indicated, particularly if hemophagocytic syndrome is present; the prognosis is generally favorable. 1

Common Pitfalls to Avoid

• Do not assume autoimmune hepatitis based solely on transaminase elevation without obtaining a complete autoantibody panel (including anti-SLA and atypical p-ANCA) and liver biopsy, as seronegative AIH accounts for 19-34% of AIH cases but requires histologic confirmation. 2

• Do not delay lymph node biopsy in favor of serologic testing alone, as tissue diagnosis is essential to exclude lymphoma, Kikuchi disease, or other lymphoproliferative disorders that require specific management. 1, 6

• Do not overlook HLH in patients with fever, lymphadenopathy, hepatosplenomegaly, and elevated transaminases; check ferritin and triglycerides immediately, as HLH can be fatal without prompt recognition and treatment. 1

• Do not attribute mild transaminase elevation to non-alcoholic fatty liver disease (NAFLD) without excluding systemic inflammatory or infectious causes, particularly when cervical lymphadenopathy is present. 3