14 Review Article Undiagnosed liver diseases Emily Gao1#, Julian Hercun2#, Theo Heller2, Sílvia Vilarinho1,3 1Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA; 2Translational Hepatology Section, National Institute of Diabetes & Digestive & Kidney Diseases, National Institute of Health, Bethesda, MD, USA; 3Department of Pathology, Yale School of Medicine, New Haven, CT, USA Contributions: (I) Conception and design: All authors; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Theo Heller, MD. Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institute of Health, Building 10, Room 10N248A 10 Center Drive, Bethesda, MD, 20814, USA. Email: [email protected]; Silvia Vilarinho, MD, PhD. Departments of Internal Medicine (Digestive Diseases) and of Pathology, Yale School of Medicine, 333 Cedar Street, LMP1080, New Haven, CT 06510, USA. Email: [email protected]. 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 Received: 10 December 2019; Accepted: 19 March 2020; Published: 05 April 2021. doi: 10.21037/tgh.2020.04.04 View this article at: http://dx.doi.org/10.21037/tgh.2020.04.04 Introduction illustrate our incomplete understanding of the overall prevalence of liver dysfunction; and at this point in time, Chronic liver disease is the 11th leading cause of death in the spectrum of molecular pathogenesis and natural history the US and its incidence has been rising in the developing of liver disease remain unexplained in a significant number world with no signs of abatement (1-3). Many patients with of patients. abnormal liver function tests are asymptomatic, making The absence of a definitive diagnosis indicates a lack the prevalence of liver dysfunction among the general of understanding as to why an individual develops liver population difficult to ascertain. In a retrospective study of disease, which severely limits appropriate treatment and 354 adult patients with abnormal liver function tests who prognostication for these patients. Firstly, when studying underwent liver biopsy, 6% of patients had normal liver idiopathic liver disease, many studies tend to agglomerate histology and 9% of patients had hepatitis of unknown all cases of idiopathic liver disease into a single group. Such etiology (4). Moreover, a prospective study of 272 adults studies compare the demographics, clinical features and with 6 months of persistently abnormal liver function tests outcomes of individuals with undiagnosed liver disease to identified no etiology for such abnormalities in nearly individuals with a well-defined diagnosis of liver disease 20% of this group of patients (5). Altogether, these studies (6-9). Secondly, many of these comparative studies tend © Translational Gastroenterology and Hepatology. All rights reserved. Transl Gastroenterol Hepatol 2021;6:28 | http://dx.doi.org/10.21037/tgh.2020.04.04 Page 2 of 14 Translational Gastroenterology and Hepatology, 2021 Table 1 A proposed approach to undiagnosed liver disease When evaluating a patient with undiagnosed liver disease, consider whether it might be… 1. A hidden liver disease Is it an underdiagnosis or a misdiagnosis of a well-characterized hepatic disease? 2. A disguised liver disease Could it be a hepatic manifestation of a well-characterized disease better known for its extra-hepatic presentation (i.e., cystic fibrosis)? 3. A known liver disease of unknown cause Is it a well-characterized liver phenotype with unknown etiology (i.e., biliary atresia, PSC)? 4. An unknown liver disease Could it be a novel liver disease with uncharacterized clinical features, natural history and unknown cause? to be limited to small case series (7-9). It is important to also discuss undiagnosed stage of liver disease and provide recognize that this approach is deeply flawed since it merges recommendations regarding how to approach liver diseases data from several diseases with distinct pathogeneses, of unknown etiology. creating an “average” of “diseases” that do not exist and therefore inapplicable to patient care. The hidden known liver diseases Cryptogenic cirrhosis (CC) defined as cirrhosis of unknown etiology after unraveling extensive testing (10) Liver disease can remain undiagnosed and undetected until exemplifies this concept. The decreasing prevalence of clinical manifestations become apparent. Common liver CC over the past 40 years reflects the progress made in diseases, such as viral hepatitis and NAFLD, can remain diagnosing idiopathic liver disease (11). Specifically, the silent for decades. These known liver diseases often evade discovery of hepatitis B virus (HBV) in 1965, hepatitis C routine detection and their diagnosis depends on improved virus (HCV) in 1989 and the concomitant development of screening and awareness. Additionally, liver related serological testing, led to the recognition that viral hepatitis mortality due to viral hepatitis might be underreported infections were responsible for a large number of cases of (13,14). This well-recognized cause of liver disease can cirrhosis. Moreover, improvement in the definition and have severe consequences in at risk populations, including identification of autoimmune hepatitis in the last three immunocompromised and chronic liver disease patients. decades and increasing recognition of non-alcoholic fatty Viral hepatitis has the potential to remain silent due liver disease (NAFLD) as a cause of hepatic dysfunction to underdiagnosis resulting from failure to screen in further explained additional cases of cirrhosis. Today, we appropriate populations or from false-negative screening all recognize that each etiology (viral, autoimmune, among tests. Although major advances in the field of chronic others) has its own distinct treatment and overall prognosis HCV infection over the last three decades have led to safe (6,12). curative therapies for millions of infected people (15) and Here, we examine several broad categories of increased public awareness, testing for HCV is undertaken undiagnosed liver disease, which span from atypical far too infrequently. In the primary care setting, there is presentations of known diseases to uncharacterized liver concerning data showing that only 16% of patients with disorders. Specifically, we describe four broad categories consistently elevated transaminases underwent serological of undiagnosed liver disease: (I) the hidden liver disease, testing for HCV (16). which consists of underdiagnosis or misdiagnosis of well- Hepatitis D virus (HDV) is also routinely undertested. characterized hepatic disease; (II) the disguised liver In a cohort of HBV positive American veterans only 7.8% disease, which includes hepatic manifestations of broader were co-tested for HDV (17), while in a European cohort well-characterized diseases better known for extrahepatic only 30% of HBV positive patients were co-tested (18), presentation (i.e., cystic fibrosis); (III) the known liver despite recommendations for more widespread HDV disease of unknown cause, such as well-characterized liver testing. Nonetheless, even if appropriate screening in at risk phenotypes with unknown etiology [i.e., biliary atresia (BA)], patients is performed, there is a possibility of false negatives. and (IV) the unknown liver diseases, encompassing novel For example, occult HBV infection, defined as detectable liver diseases with uncharacterized phenotypic features, HBV DNA in HBV surface antigen (HBsAg) negative natural history and unknown cause (Table 1). Lastly, we will individuals, remains a public health danger in HBV endemic © Translational Gastroenterology and Hepatology. All rights reserved. Transl Gastroenterol Hepatol 2021;6:28 | http://dx.doi.org/10.21037/tgh.2020.04.04 Translational Gastroenterology and Hepatology, 2021 Page 3 of 14 regions such as Africa and Asia, where recent population potentially underrepresented and improving HEV RNA studies suggest a prevalence of 8–26% (19-23). screening tools, many have advocated for a more widespread Failure to screen for or to detect viral hepatitis occurs testing of blood products, as already established in several not only in asymptomatic patients but can lead to missed European countries including Ireland, France, Germany, diagnoses or misdiagnosis in