Undiagnosed liver diseases

Abstract

The landscape of chronic liver disease has drastically changed over the past 20 years, largely due to advances in antiviral therapy and the rise of metabolic syndrome and associated non-alcoholic fatty liver disease (NAFLD). Despite advances in the diagnosis and treatment of a variety of liver diseases, the burden of chronic liver disease is increasing worldwide. The first step to addressing any disease is accurate diagnosis. Here, we discuss liver diseases that remain undiagnosed, either because they are difficult to diagnose or due to hepatic manifestations of an unrecognized systemic disease. Additionally, their underlying etiology may remain unknown or they represent previously uncharacterized and therefore novel liver diseases. Our goal is to provide a framework for approaching undiagnosed liver diseases which elude standard hepatic diagnostic work-up and whose patterns of disease are often overlooked.

Keywords: Idiopathic liver disease; cryptogenic cirrhosis (CC); unmet medical need.

Figure 1

Reticulin stain of a liver biopsy from a patient with sickle cell disease demonstrating nodular regenerative hyperplasia (NRH). In the center of the slide, hyperplastic hepatocytes can be identified creating a nodule without any identifiable fibrosis. (Slide courtesy of Dr. David Kleiner). 200× magnification.

Figure 2

Representation of the rising number of liver disease-causing genes discovered since 1985 based on OMIM (Online Mendelian Inheritance in Man) data (last accessed in August 31, 2019). Specifically, genes and phenotypes associated with “cirrhosis” were searched in the OMIM database. These genes associated with liver disease were further investigated in PubMed to find the original discovery date. Somatic mutations, gene associations, and cases in which there was limited evidence of liver disease-gene causality were removed.