What is the differential diagnosis for a patient with a history of alcohol excess, hepatosplenomegaly, fever, persistent cough, leukocytosis, and multiple enlarged lymph nodes in the abdomen?

Differential Diagnosis for Hepatosplenomegaly with Fever, Persistent Cough, Leukocytosis, Target Cells, and Abdominal Lymphadenopathy in a Patient with Chronic Alcohol Excess

The most critical differential diagnoses to consider are: (1) alcohol-associated cirrhosis with portal hypertension complicated by infection, (2) hemophagocytic lymphohistiocytosis (HLH), (3) lymphoproliferative disorders (lymphoma or chronic lymphocytic leukemia), and (4) disseminated tuberculosis or other chronic infections, with alcohol-associated liver disease being the most likely primary diagnosis given the 2-year history of alcohol excess. 1, 2

Primary Alcohol-Related Considerations

Alcohol-Associated Cirrhosis with Complications

• Chronic alcohol excess for 2 years with hepatosplenomegaly strongly suggests alcohol-associated cirrhosis (AC) with portal hypertension, which commonly presents with splenomegaly due to portal hypertension and hepatomegaly from fatty infiltration or cirrhotic changes 1
• The presence of target cells indicates chronic liver disease with hyposplenism or altered red blood cell membrane lipid composition, consistent with cirrhosis 1
• Fever with negative blood cultures in a cirrhotic patient raises concern for spontaneous bacterial peritonitis, occult infection, or hepatic abscess that requires imaging evaluation 3
• Leukocytosis in this context may represent reactive changes to infection, though the AST:ALT ratio should be checked—a ratio >2 is highly suggestive of alcohol-associated liver disease 1

Alcoholic Hepatitis

• Alcoholic hepatitis presents with fever, hepatomegaly, leukocytosis, and jaundice, though the presence of significant splenomegaly and abdominal lymphadenopathy makes this less likely as the sole diagnosis 1
• AST levels are typically 2-6 times upper limit of normal with AST:ALT ratio >2 in approximately 70% of cases 1

Immune Dysregulation and Hematologic Disorders

Hemophagocytic Lymphohistiocytosis (HLH)

• HLH presents with high fever, hepatosplenomegaly, and leukocytosis (or cytopenias), making it a critical consideration 1, 2
• The diagnostic algorithm for immune dysregulation syndromes indicates that acute presentation with high fever, toxic appearance, and lymphoproliferation (hepatosplenomegaly, lymphadenopathy) should prompt consideration of HLH 1
• Check ferritin (markedly elevated >500-10,000 ng/mL), triglycerides (elevated), fibrinogen (decreased), and perform bone marrow examination looking for hemophagocytosis 2
• Alcohol excess can trigger secondary HLH through immune dysregulation 1

Lymphoproliferative Disorders

• Lymphoma and chronic lymphocytic leukemia are leading causes of hepatosplenomegaly with lymphadenopathy, particularly with constitutional symptoms like fever 2
• The presence of multiple enlarged abdominal lymph nodes strongly supports this diagnosis 2
• Immediate evaluation requires complete blood count with manual differential to identify abnormal lymphocytes, followed by bone marrow biopsy if cytopenias are present 2
• Peripheral blood smear should be examined for atypical lymphocytes or lymphoblasts 2

Infectious Etiologies

Disseminated Tuberculosis

• Persistent cough with fever, hepatosplenomegaly, and abdominal lymphadenopathy is classic for disseminated tuberculosis, especially in immunocompromised patients (alcohol excess causes immune dysfunction) 4
• Despite normal HRCT chest, miliary TB can present with minimal pulmonary findings initially 4
• Bone marrow biopsy with acid-fast bacilli staining and mycobacterial cultures is essential, as organisms may be identified within macrophages 4

Visceral Leishmaniasis

• In patients from or traveling to Mediterranean regions, visceral leishmaniasis presents with prolonged fever, hepatosplenomegaly, pancytopenia (or leukocytosis), and weight loss 4
• Bone marrow examination reveals macrophages containing intracellular Leishmania organisms 4
• This diagnosis must be considered based on geographic exposure history 4

Pyogenic Liver Abscess

• Fever with hepatomegaly and negative blood cultures should prompt abdominal imaging to exclude pyogenic liver abscess, which can present with leukocytosis 3
• Abdominal lymphadenopathy may represent reactive changes 3
• Ultrasound with Doppler or CT abdomen is mandatory to identify focal hepatic lesions 3, 2

Metabolic Storage Disorders (Less Likely but Consider)

Lysosomal Storage Diseases

• Gaucher disease and Niemann-Pick disease present with hepatosplenomegaly, but typically manifest earlier in life or with more prominent neurological symptoms 5, 6, 7
• The 2-year timeline with alcohol excess makes this less likely, but if thrombocytopenia is present with bone abnormalities, check leukocyte β-glucocerebrosidase activity 5
• Bone marrow biopsy showing sea-blue histiocytes or Gaucher cells would confirm storage disease 6, 7

Diagnostic Algorithm

Immediate Laboratory Evaluation

1. Complete blood count with manual differential to assess for cytopenias, atypical cells, or true leukocytosis 2
2. Comprehensive metabolic panel including AST, ALT, bilirubin, alkaline phosphatase, albumin, and INR to assess liver synthetic function and calculate AST:ALT ratio 1, 2
3. Ferritin, triglycerides, fibrinogen, and LDH to evaluate for HLH 2
4. Peripheral blood smear to identify target cells, atypical lymphocytes, or intracellular organisms 2, 4

Imaging Studies

1. Abdominal ultrasound with Doppler as initial imaging to confirm hepatosplenomegaly, assess portal flow, and identify focal lesions 2
2. CT abdomen and pelvis with contrast to characterize abdominal lymphadenopathy and exclude abscess or malignancy 3, 2
3. Consider vibration-controlled transient elastography (VCTE) to assess for cirrhosis and portal hypertension 2

Invasive Diagnostic Procedures

1. Bone marrow aspiration and biopsy with cytogenetic analysis is mandatory if cytopenias are present or if HLH, lymphoproliferative disorder, or disseminated infection is suspected 2, 4
2. Lymph node biopsy (if accessible) for flow cytometry, immunohistochemistry, and cultures 2
3. Liver biopsy may be needed if diagnosis remains unclear after initial workup, particularly to distinguish alcoholic hepatitis from other causes 1

Critical Pitfalls to Avoid

• Do not attribute all findings to alcohol-associated liver disease without excluding infection, malignancy, or HLH—these conditions require urgent specific therapy 1, 2
• Do not delay bone marrow examination when fever and hepatosplenomegaly are accompanied by cytopenias or unexplained leukocytosis—this combination mandates immediate evaluation 2
• Normal chest HRCT does not exclude disseminated tuberculosis—extrapulmonary TB requires bone marrow or lymph node sampling 4
• Negative blood cultures do not exclude serious infection—consider occult abscess, tuberculosis, or fungal infections in immunocompromised alcoholic patients 3, 4
• Target cells indicate chronic liver disease but do not specify etiology—comprehensive workup is still required 1

Referral Strategy

• Initial referral should be to hepatology/gastroenterology as the liver is often the primary affected organ in hepatosplenomegaly 8, 2
• Immediate hematology/oncology consultation is required if peripheral smear shows abnormal cells, pancytopenia is present, or HLH is suspected 2
• Infectious disease consultation is warranted for persistent fever with negative cultures and concern for disseminated infection 4