What are the causes of Budd Chiari syndrome in patients with various ages and medical histories, including thrombophilic conditions, cancer, and inflammatory diseases?

What Causes Budd-Chiari Syndrome

Budd-Chiari syndrome is caused by prothrombotic conditions in up to 84% of cases, with myeloproliferative neoplasms being the single most important cause (present in approximately 49% of patients), followed by inherited thrombophilias and paroxysmal nocturnal hemoglobinuria. 1, 2

Primary Etiological Categories

The causes of Budd-Chiari syndrome can be systematically divided into local and systemic factors, with most patients having multiple concurrent risk factors 1:

Systemic Prothrombotic Conditions (Most Common)

Myeloproliferative Neoplasms (49% of cases):

• Polycythemia vera is the most frequently associated subtype 2, 3
• The JAK2V617F mutation is detected in approximately 29% of all Budd-Chiari patients, serving as a molecular marker for underlying MPN 3
• Critical pitfall: Peripheral blood counts may appear normal despite underlying MPN due to concurrent hypersplenism, hemodilution from ascites, or occult gastrointestinal bleeding—this can mask the characteristic thrombocytosis and erythrocytosis 3

Inherited Thrombophilias (21% of cases):

• Factor V Leiden mutation has a 7-32% prevalence, conferring 4-11 fold increased risk 3
• Prothrombin G20210A gene variant confers 2-fold increased risk 1, 3
• Protein C deficiency, protein S deficiency, and antithrombin deficiency (0-5% prevalence) 1, 3

Paroxysmal Nocturnal Hemoglobinuria (19% of cases):

• Represents a substantial comorbidity requiring specific flow cytometry testing 3

Acquired Thrombophilias:

• Antiphospholipid antibodies have an estimated 5-15% prevalence 1, 3
• Confirmation requires repeat testing after 12 weeks per current diagnostic criteria 1, 3

Local Risk Factors

Mechanical Obstruction:

• Solid malignancies or cysts that compress the hepatic venous tract 1
• Webs (membranous obstruction) of the inferior vena cava, particularly in Asian populations 1
• Hydatid cysts 1

Inflammatory Conditions:

• Intra-abdominal inflammatory conditions 1
• Behçet disease, especially in Asia 1

Iatrogenic/Procedural:

• Intra-abdominal surgery 1
• In children: neonatal sepsis and umbilical catheterization 1

Multifactorial Nature

The etiology is multifactorial in the majority of patients 1:

• 46% of Budd-Chiari patients have a combination of two or more genetic or acquired prothrombotic factors 1
• 18% of patients have three or more concurrent risk factors 1
• Over 60% of patients with inherited thrombophilia have at least one additional risk factor 1
• Approximately 15% of cases have simultaneous portal vein thrombosis at presentation, which worsens prognosis 1, 3

Mandatory Diagnostic Workup

All patients require comprehensive investigation for both local and systemic prothrombotic factors, and identification of one risk factor should not deter from looking for additional risk factors 1:

Thrombophilia screening must include:

• Protein S, protein C, and antithrombin levels 1, 3
• Factor V Leiden mutation 1, 3
• Prothrombin G20210A gene variant 1, 3
• Antiphospholipid antibodies (with repeat testing at 12 weeks if positive) 1, 3

Myeloproliferative neoplasm testing:

• JAK2V617F mutation testing in all patients regardless of peripheral blood counts 1, 3
• If JAK2V617F negative, proceed to calreticulin mutation screening 1
• If both negative, consider bone marrow histology with hematology referral 1, 3

Additional testing:

• Flow cytometry for paroxysmal nocturnal hemoglobinuria 3
• Investigation for local risk factors including intra-abdominal inflammatory conditions and abdominal malignancies 1

Geographic Variations

Important caveat: Presentation differs between Western and Eastern countries 4:

• In Asia, Behçet disease, IVC webs (membranous obstruction), and hydatid cysts are more common etiological factors 1
• Western countries show higher prevalence of myeloproliferative neoplasms and inherited thrombophilias 1