What are the causes of splenomegaly in a 40-year-old woman with a history of gastrointestinal tuberculosis?

Causes of Splenomegaly in a 40-Year-Old Female with History of GI TB

In a 40-year-old woman with prior gastrointestinal tuberculosis, the most critical consideration is recurrent or disseminated tuberculosis involving the spleen, though portal hypertension from hepatic TB sequelae, hematologic disorders, and storage diseases must also be systematically excluded.

Direct Tuberculous Involvement

Splenic Tuberculosis

• Isolated splenic TB can occur even in immunocompetent individuals and may present with fever, left upper quadrant pain, and splenomegaly without obvious pulmonary disease 1, 2.
• Splenic TB typically manifests as part of disseminated disease but can rarely present as primary isolated involvement 3, 1.
• Massive hepatosplenomegaly with hepatic failure has been documented in disseminated TB, though this represents a rare and severe presentation 4.
• Extrasplenic involvement is usually present in splenic TB, including enlarged splenic hilar lymph nodes, cystic lymph nodes, or hepatic lesions, though these may not be apparent initially 2.

Clinical Presentation

• Fever of unknown origin combined with splenomegaly should raise strong suspicion for splenic TB in endemic areas or patients with prior TB history 2.
• Hypersplenism with bleeding manifestations occurs in approximately 38% of splenic TB cases (3 of 8 patients in one series) 2.
• Radiologic evaluation may demonstrate splenic lesions (hypodense areas on CT), though imaging can be normal in early disease 3, 2.

Hepatic Sequelae Leading to Portal Hypertension

TB-Related Liver Disease

• GI tuberculosis can cause hepatic involvement through hematogenous spread or direct extension, potentially leading to hepatic fibrosis and cirrhosis 5.
• Cirrhosis with portal hypertension is a common cause of splenomegaly and should be evaluated with liver function tests and imaging 6, 7.
• Portal hypertension creates a self-perpetuating cycle: splenic congestion enlarges the spleen, which increases splenic arterial inflow, further aggravating portal pressure 7.

Idiopathic Non-Cirrhotic Portal Hypertension (INCPH)

• INCPH produces more pronounced splenomegaly than cirrhosis and may present with isolated splenomegaly before other liver disease signs 7.
• Liver stiffness on transient elastography is typically low (<12 kPa) in INCPH, helping differentiate it from cirrhosis despite similar portal hypertension 7.

Hematologic Disorders

Myeloproliferative Neoplasms

• Primary myelofibrosis is the most common hematologic cause of massive splenomegaly, frequently producing enlargement >10 cm below the costal margin 8.
• JAK2 V617F mutation testing should be performed even when complete blood count is normal, as the mutation can be detected before hematologic abnormalities appear 8.
• Normal peripheral counts do not exclude myeloproliferative neoplasms because splenic sequestration can mask underlying marrow proliferation 8.

Lymphoproliferative Disorders

• Lymphomas represent a major proportion of malignant causes of splenomegaly in adults and should be considered, especially with lymphadenopathy or B-symptoms 6, 8.

Storage Disorders

Lysosomal Storage Diseases

• Acid sphingomyelinase deficiency (ASMD/Niemann-Pick disease) typically causes massive hepatosplenomegaly, often >10× normal organ size 9, 8.
• Gaucher disease results in significant splenomegaly in approximately 90% of patients and should be considered in the differential 8.
• Mixed dyslipidemia (increased LDL, VLDL, triglycerides; decreased HDL) is characteristic of storage disorders like ASMD 9.

Diagnostic Algorithm

First-Line Evaluation

• Abdominal ultrasound with Doppler to confirm splenomegaly (>13 cm vertical length), assess portal hypertension signs (portal flow reversal, reduced velocity), and identify splenic lesions 6, 8, 7.
• Complete blood count to detect cytopenias (anemia, thrombocytopenia, leukopenia) suggesting hypersplenism or hematologic malignancy 6, 8.
• Liver function tests (transaminases, bilirubin, alkaline phosphatase) to evaluate hepatic involvement and cirrhosis 6, 8.
• Chest X-ray to assess for active pulmonary TB, as pulmonary disease is present in less than half of GI TB cases 5.

Second-Line Testing Based on Initial Findings

If imaging shows splenic lesions or fever is present:

• CT chest and abdomen to identify splenic abscesses, lymphadenopathy, or hepatic lesions suggesting TB 3, 2.
• Tuberculin skin test or interferon-gamma release assay (IGRA) to support TB diagnosis 9.
• Consider diagnostic laparoscopy with splenic biopsy if imaging is suggestive but non-diagnostic, as histopathology remains the gold standard 3, 1, 2.

If portal hypertension is suspected:

• Transient elastography to measure liver stiffness; values >20-21 kPa predict clinically significant portal hypertension 7.
• Upper endoscopy to evaluate for esophageal varices if portal hypertension is confirmed 7.

If blood counts are normal but splenomegaly is massive:

• JAK2 V617F, CALR, and MPL mutation testing to exclude myeloproliferative neoplasms 8.
• Bone marrow examination if patient is >60 years or has systemic symptoms (fever, weight loss, night sweats) 6, 8.

If cytopenias are present:

• Peripheral blood smear to identify abnormal cells (hairy cells, blasts) or leukoerythroblastic picture 8.
• Flow cytometry (CD19, CD20, CD11c, CD25, CD103) if lymphoproliferative disorder is suspected 8.

Third-Line/Specialized Testing

• Lipid profile if storage disorder is suspected; severe decreases in HDL cholesterol suggest ASMD 9.
• Genetic testing for SMPD1 when ASMD is clinically suspected 8.

Critical Pitfalls to Avoid

• Do not assume prior TB treatment excludes recurrent disease; splenic TB can develop months to years after initial GI TB, especially if treatment was incomplete 1, 2.
• Absence of pulmonary TB does not rule out splenic involvement; extrapulmonary TB frequently occurs without active lung disease 5, 1, 2.
• Moderate or massive splenomegaly (>3% of abdominal examination) essentially excludes immune thrombocytopenic purpura and mandates investigation for structural causes 8.
• Normal liver enzymes do not exclude cirrhosis or portal hypertension; imaging and elastography are essential 7.
• Splenic sequestration can normalize or reduce blood counts in myeloproliferative disorders, masking the underlying proliferative process 8.