Precision medicine in nonalcoholic fatty liver disease.

Abstract

Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals. You can match a blood transfusion to a blood type - that was an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature? - President Obama, January 30, 2015 In 2011 in the USA, supported by the National Academy of Sciences and the National Institutes of Health, the Committee on A Framework for Developing a New Taxonomy of Disease issued a document entitled: Toward Precision Medicine. Building a knowledge network for biomedical research and a new taxonomy of disease.1 The document stated that the creation of a new taxonomy required two key components: an Information Commons which rendered data on large patient populations extensively available for research use and a Knowledge Network adding further value to such data by pinpointing their interrelationships integrated with updated understanding of basic biological phenomena.1 Large databases can be analyzed through systems biology approaches that provide an integrative analysis of different types of data, therefore being able to yield novel understanding of complex biological systems.2 Similarly, systems medicine approaches have the potential for promoting the development of (personalized and) precision medicine in various medical fields, notably including metabolic diseases, insulin resistance, obesity, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis NAFLD/NASH.2 Shaped by big data technology (genomics, epigenomics, transcriptomics, proteomics, lipidomics, metabolomics, microbiomics, exposomics, and pharmacogenomics), precision medicine represents a shift of paradigm from medical practice directed by guidelines, to patient-tailored approaches.3 NAFLD is a nomenclature going back to the 1980s: NAFLD essentially describes a clinico-pathological disease entity featuring an alcohol-like hepato-histological basis (fatty changes with/without ballooning, modest inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma) combined with the exclusion of competing causes of (steatogenic) liver disease.4 How far one should go in ruling out such competing etiologies of liver disease remains poorly defined. However, the exclusion of hepatotoxic amounts of alcohol is a mainstay of NAFLD definition, although the biological rationale in distinguishing NAFLD from alcohol-related fatty liver disease remains uncertain.5 Pathogenic and clinical variability of disease spanning from hepatic disease6, 7 to systemic manifestations is one of the earliest identified and most impressive features of NAFLD and NASH (i.e. the most rapidly progressive form of NAFLD). Systemic manifestations comprise an increased risk of developing incident cardio-metabolic disease, chronic kidney injury, and extra-hepatic cancer.8-11 While faithfully mirroring multiple layers of pathogenic determinants—including hepatocyte metabolic stress; cellular adaptive mechanisms and cell death; inflammatory changes; and development of fibrosis12—such a clinical variability also poses a formidable challenge for clinicians aiming at tailoring the diagnostic, therapeutic, and follow-up schedules to the individual patient. Recently, pioneering attempts to establish the scope of precision medicine approaches in the NAFLD arena have been outlined.13 These include renaming NAFLD to MAFLD (i.e. metabolic [associated] fatty liver disease) which aims at including a positive criterion in the diagnostic process: metabolic as opposed to nonalcoholic.14, 15 Paralleling nosographic concerns, there is increased awareness among researchers and clinicians that a spectrum of biological variables concur to determine NAFLD/MAFLD heterogeneity: sex and reproductive status, genetics, intestinal microbiota, endocrine-metabolic status, and physical activity.13 At the time of this writing (December 18, 2021), with the entry item “Precision Medicine” [Title], 4128 results were identified in a PubMed Research. The large majority of these were published from 2016 onwards, probably as a result of the impetus given to precision medicine by President Obama in 2015. However, only 11 results out of these 4128 articles dealt with NAFLD (“precision medicine” [Title] AND “NAFLD” [Title/Abstract]), suggesting that we still have a long way to go along this research path. The scope of precision medicine approaches should best be articulated into two different and strictly interconnected layers: diagnosis and management. What we need to implement is a consistent classification system that can identify homogeneous patient populations. To this end, what is immediately available is a descriptive classification system, the so called “LDE,” namely, Liver; Determinants; and Extra-hepatic.5, 13, 14 However, the LDE classification system (or similarly structured algorithms) is only a first step forward in the process of obtaining individual NAFLD patients' metabolic identity card which would allow the selection of fairly homogeneous patient populations to recruit in clinical trials. This aim will eventually be achieved by clearly distinguishing some key variables. For example, attempts to better define metabolic components may potentially lead to discovering a metabolic signature.16-18 This should be combined with genetic risk scores.19 Moreover, it is of fundamental importance to identify non-invasive biomarkers which are capable of detecting progression from simple steatosis to NASH, which is associated with an increased risk of hepatic and extra-hepatic clinical events.20, 21 Similarly, it is important to integrate well defined hepato-histological variables, such as zonation in NASH,22 into a more comprehensive view of risk stratification of NAFLD/NASH/MAFLD in the individual patient. Additional biomarkers which are relevant for precision medicine approaches include serum lipidome analysis (for the diagnosis of NAFL-associated hepatocellular carcinoma), bile acids, and gut microbiota signature.23-25 Research in the precision medicine arena may strongly be promoted by the finding of activated pathways in the liver tissue of any given patient. However, this would hardly be achievable in clinical practice, where “liquid biopsy” could be a reasonable alternative option to systematic liver tissue sampling given that there are inflammatory biomarkers available.26 Additionally, promising data have been reported regarding the diagnostic accuracy in identifying fibrosis non-invasively.27-29 Similarly, the APAC score (combining age, soluble platelet-derived growth factor receptor beta, alpha-fetoprotein, and creatinine), was able to accurately identify, among individuals with cirrhosis, those patients with HCC.30 These biomarkers, to which probably others will be added in the future,31 ideally complement available imaging techniques which are very accurate in identifying even minor degrees of liver fatty changes.32, 33 The correction of the determinants of NAFLD and NASH that are specific to the individual patient has fundamental therapeutic importance. This could be accomplished, for example, through finely modulating either the gut microbiota; or the activity of those genes involved in the development and progression of disease.34-37 However, it should be highlighted that the safe and effective use of various therapeutics is hampered by individual variability in response to treatment.38 This, in its turn, will result from variations due to genetics, ethnicity, age, sex, hepatic and renal detoxifying capacity, diet, environmental chemicals, alcohol, drug–drug interactions, drug dynamics, and kinetics.39 All these must be taken into account in the NAFLD arena, where variable pathogenic pathways, associated with heterogeneous metabolic co-morbidities, and a long-lasting course of disease, have collectively hindered the discovery of effective drug approaches till now.39 Bringing this research further, a recent network meta-analysis has reported that semaglutide, liraglutide and vitamin E plus pioglitazone ranked as the most effective interventions for achieving NASH resolution.40 However, in order to maximize the expected therapeutic benefits, while decreasing the risks of side effects and non-response, these drugs should best be administered to the right patient at the right time. Defining this is the specific task of precision medicine in the NAFLD arena. We also need an improved understanding of the molecular pathogenic pathways underlying the development of individual elementary histological hepatic lesions: steatosis; ballooning; inflammatory changes; and fibrosis whose metabolic correlates have been characterized precisely.41, 42 These metabolic correlations pave the way for personalized histology-based management approaches through pharmacological correction of those metabolic derangements associated with given liver histology lesions.42 The most important therapeutic target, among the elementary histological hepatic lesions of NAFLD/NASH, is fibrosis, given that it dictates the course of both hepatic and extra-hepatic manifestations and complications of disease.43, 44 However, some ant-fibrotic drug agent NASH trials have yielded disappointing results.45 Therefore, new hope comes from intensive lifestyle treatment leading to BMI reduction,46-50 lanifibranor, obeticholic acid, pioglitazone and vitamin E,40 or drug combination therapies.51 Clearly, research and development of new and accurate serum biomarkers and imaging techniques capable of evaluating the dynamics of hepatic fibrogenesis in NASH will improve diagnosis, classification and follow-up of patients with progressive disease. This, in its turn, promises to facilitate the development of novel anti-fibrotic drugs and the implementation of a truly personalized anti-fibrotic therapy, which is urgently needed for patients who are at risk of rapidly progressive disease.52 However, evolution has selected redundancy of metabolic networks as a means to cope with the disruption of key metabolic pathways.53 This renders the strategy of blocking the steatogenic process and its biological consequences at different levels more attractive (e.g. hepatocyte defattening, restraining metaflammation, deactivation of stellate cells, and impaired cancerogenesis).54 Similarly, in patients with MAFLD/NAFLD, compared with individual drug agents, combined therapeutic strategies targeting multiple fibrogenic networks appear more promising in successfully carrying out antifibrotic interventions.55 In addition, such direct anti-fibrotic strategies, in their turn, should probably be associated with drugs targeting those hepatometabolic and steatohepatitis pathomechanisms (such as hepatocyte stress and cell death, gluco- and lipotoxicity, inflammation) which continuously drive compensatory fibrogenic networks.56 Finally, a key determinant of precision medicine is tailored therapy based on accurate (non-invasive) assessment of treatment response53, 54 and pharmaco-genomics to provide a specific diet and drug treatment regime suitable to the individual NAFLD patient's genetic makeup.39 Progress in the AI field, by generating predictive models more precisely than conventional approached, promises to strongly improve the practice of precision medicine in hepatology.3 For example, AI might use imaging data from various techniques (ultrasonography, computed tomography, and magnetic resonance) to sustain the differential diagnosis of both diffuse and focal liver disease.3 Furthermore, the AI algorithms, using electronic health records and pathological data, may also anticipate NAFLD diagnosis and assess outcome trajectories.3 NAFLD is a systemic disorder with variable disease outcomes.55 Advances in the research of novel investigation tools and electronic health records sustain a paradigm shift from guideline-directed to patient-specific precision medicine approaches.3 While exhibiting a high potential, application of artificial intelligence poses major concerns regarding the steps from data processing, quality control and appropriate labeling, to sampling biases.3 Additionally, proposals and validation of algorithms are also challenging, as are any attempts to apply these to real-world hepatological practice.3 However, with the backset of improved approaches to personalized medicine in metabolic disorders and target organ damage, precision medicine strategies promise novel therapeutic discoveries modeled by systems biology, systems pharmacology and systems medicine approaches.3, 38, 56-59