Epidemiology of liver disease
The incidence of liver disease is high and continues to increase. The World Health Organization estimates that 5.3% of the world population is infected with hepatitis B virus (HBV) and 3.2% with hepatitis C virus (HCV), infections leading to chronic liver inflammation. Hepatocellular carcinoma (HCC), the primary form of liver cancer, is the third most common cause of cancer-related deaths worldwide with about 600,000 patients dying from the disease annually. The incidence rate of HCC has increased by 3.5 fold in the past 25 years in the United States. Non-alcoholic fatty liver disease (NAFLD) may affect 10–20% of the population, largely as a consequence of the worldwide crisis in obesity and diabetes. Therefore, overall, we can estimate that 1 out of 5 persons is afflicted by a disease of some type affecting the liver.
Needs in daily clinical practice
Most importantly, there are urgent needs for the clinical management of patients with liver diseases as most liver diseases remain poorly diagnosed, staged and treated. The development of diagnostic biomarkers, predictors of disease progression or new therapeutic targets is needed for all forms of liver injury from chronic viral infection, to liver fibrosis, steatosis, cirrhosis and cancer. The development of new therapeutic agents is critical for further improvement in the management of chronic hepatitis C as current therapies have low efficacy in certain patient subgroups and are associated with frequent side effects affecting the patient's quality of life. NAFLD is a spectrum of disorders ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Steatosis has been described as histological changes within the liver and commonly exists in patients who remain asymptomatic. However, up to 20% patients with NASH may develop cirrhosis and, of these patients who develop cirrhosis, 30–40% may suffer liver-related mortality. Similarly, fibrosis ranges from mild to severe, with cirrhosis being defined as the most advanced form of progressive hepatic fibrosis, and staging of fibrosis remains largely based on histological examination of liver biopsies. Therefore, the development of new effective means to stage NAFLD or fibrosis is a matter of significant clinical importance. These clinical problems have only rarely been tackled using proteomics. It was therefore important to include a study on biomarkers distinguishing NAFLD and NASH patients in this Special Issue (Rodríguez-Suárez et al.), with the hope to further stimulate this line of research. To date, clinical proteomics studies targeting liver diseases have focused mainly on HCC biomarkers. A majority of patients diagnosed with HCC present at an advanced stage with poor prognosis. Early diagnosis and definitive treatment remains the key to long-term outcome. HCC develops on the background of liver cirrhosis. Improvement in clinical management of patients with liver cirrhosis and the control of related complications are the key for the rising incidence of HCC. Furthermore, the simultaneous presence of cirrhosis in the patients complicates their management and treatment options. Studies on liver cirrhosis are therefore also of major importance. As presented in a review and associated article by André Klein and colleagues, the total serum N-glycome differs extensively in cirrhosis. Extensive information on N-glycan structures, specific enzymatic glycosyltransferase activity with disease stage have been generated and translated clinically at the bedside. These studies also highlight the extreme diversity of the primary structure of glycans.
Confounding factors: the major challenge for biomarker discovery in liver disease
A major challenge in clinical proteomics studies targeting liver diseases and aimed at biomarker discovery is the number of confounding variables and background liver changes. In liver injury, fat accumulation, inflammation, necrosis, apoptosis, proliferation, fibrosis, viral replication can all occur simultaneously. HCC develops on the background of liver cirrhosis caused by HBV and HCV hepatitis, high consumption of alcohol or NASH. In general, insulin resistance is implicated in the pathogenesis of NAFLD. A role of hepatic steatosis in the pathogenesis of chronic hepatitis C has also been shown, implying hepatitis C as a metabolic disease. As a consequence, progress has been slow demonstrating the need for novel strategies and careful experimental design. Integrative studies using proteomics and basic cellular biology or other growing fields such as imaging and mouse models will contribute to our understanding of the liver biology. The ability to understand the underlying molecular dysfunction in human disease (signaling pathways, protein-protein interaction networks) should accelerate the translation of basic discoveries into daily clinical practice. Liao et al. show how mouse models of liver disease can be used to provide valuable functional information and therefore help improve current concepts for prevention and screening. In a review and associated article, Juan Falcon, Jose Mato and colleagues describe how proteomic analysis of extracellular, circulating or urinary vesicles can be a powerful new path to biomarker discovery.
Liver proteomics: a tool to monitor human cancer
The last topic covered in this special issue is related to the fact that the liver displays the main digestive function for the metabolism of most substances but also undertakes a myriad of functions beyond digestion, such as production of red blood cells during embryonic development, production of numerous plasma proteins, and detoxification of xenobiotics. The liver is the most effective site for phagocytosis of solid material and the guardian interposed between the digestive tract and the rest of the body. Therefore many proteins in plasma and synthesized in the liver change with hepatotoxicity, systemic responses to inflammation and disease processes in organs other than the liver. A review by Pauline Rudd, Rosa Peracaula and colleagues reminds us that acute phase proteins are synthesized by the liver and that during chronic disease may contribute to disease progression but also present novel data of glycosylation changes occur on acute phase proteins, including disease specific glycosylation changes, highlighting their potential utility as prognostic markers. An associated article by the same authors further describes stage specific glycosylation changes of acute phase protein in pancreatic cancer and chronic pancreatitis.
In conclusion, this Special Issue, structured around a combination of reviews and topic-associated articles, is aimed at encouraging clinical proteomics studies directed to the vast area of liver disease research but also at highlighting the critical role played by the liver as a sensor of human diseases. Efforts to translate proteomics studies into daily clinical practice would benefit from studies aimed at better understanding the relationship between protein dynamic in blood and protein synthesis and processing in the liver and the role of the different liver cell types in disease development and progression.