Enlarged Spleen Causes. The causes of splenomegaly vary widely and range from malignancy (cancers), infections, congestion (increased blood flow), infiltration of the spleen from other diseases, inflammatory conditions, and blood cell diseases. Some of the most common causes of an enlarged spleen include the following: liver disease (cirrhosis due to chronic hepatitis B, chronic hepatitis C, fatty liver, long standing alcohol abuse); blood cancers (lymphoma, leukemia, myelofibrosis);