The liver is commonly involved in systemic diseases, but frequently liver injury can be clinically silent. In patients with clinical symptoms suggestive of liver involvement, the symptoms are often nonspecific and overlap with those due to the underlying systemic diseases. Liver biopsy is a powerful diagnostic modality in aiding in the diagnosis. The liver has limited mechanisms in responding to injury; therefore, many insults often create overlapping histologic patterns. The histologic interpretation of a liver biopsy may be nonspecific and as such, clinicians are often frustrated by a descriptive diagnosis or a list of generic differential diagnoses. Pathologists should always interpret the pattern of liver injury in the clinical context, including the presence of systemic diseases and corresponding treatments. Communication between clinicians and pathologists is essential to reach an accurate diagnosis of the liver disease on the liver biopsy in a patient with systemic disease. Admittedly, although liver biopsy often reveals nonspecific reactive changes in patients with systemic disease and abnormal liver function tests, it is the only way of offering a specific diagnosis to guide clinicians in the proper treatment in some cases.