The development of liver dysfunction in patients having various systemic diseases is common and has a broad differential diagnosis, at times being the initial manifestation of the disorder. Liver injury associated with systemic lupus erythematosus is heterogeneous and may present with nonspecific histology. Differentiating autoimmune hepatitis from lupus hepatitis is challenging on histologic grounds alone. Other systemic diseases that may present mostly with nonspecific findings are rheumatoid arthritis and celiac disease. More recently COVID-19 cholangiopathy and secondary sclerosing cholangitis have become increasingly recognized as distinct liver conditions. Many patients may also have intrinsic liver disease or may develop drug-induced liver injury from the treatment of the systemic disease. Timely identification of the cause of the liver dysfunction is essential and liver biopsy may help the clinician in diagnosis and management.