Nonalcoholic Fatty Liver Disease in 2020

Nonalcoholic fatty liver disease (NAFLD) has taken its place as one of the top GI and liver disorders on the minds of clinicians, researchers and the pharmaceutical industry. The global focus on metabolic liver disease is appropriate, given that NAFLD affects roughly 25% of the world’s population and has become a main focus in liver transplant programs. Efforts to understand the nature of the disease and to improve diagnostics and therapeutics are progressing at an extremely rapid pace; thus, it is important to periodically summarize and reflect on these developments.

Our vision for this special issue of Gastroenterology was to provide an up-to-date resource for clinicians and researchers on the risk factors, natural history, diagnosis and treatment of NAFLD. In addition, we aimed to highlight a selection of scientific topics pertinent to the development and progression of NAFLD: adipose tissue-liver interactions, the gut microbiome, and factors that lead to hepatic fibrogenesis given its importance to patient outcome. In the category of pathophysiology we also wished to showcase some newer concepts pertinent to NAFLD: the importance of circadian rhythms in disease development and treatment, and the notion that the liver plays a central role in the extrahepatic complications of fatty liver disease including cardiovascular and central nervous system disease. From a scientific and clinical perspective our goal was to provide a map of the complex interactions among factors within and outside the liver in defining the disease course and outcomes in NAFLD.

These links are highlighted in ten expert review articles. The issue begins with an overview of the state of NAFLD as we understand it in 2020, authored by Thomas Cotter and Mary Rinella. They emphasize the common metabolic risk factors for NAFLD, but also note variability in NAFLD phenotypes that are likely the result of genetic and environmental influences. They underscore the propensity for NAFLD patients to develop cardiovascular disease and malignancy, which currently pose a greater mortality risk than liver disease. For the practitioner these experts offer guidance on the diagnosis of NAFLD, and in particular the use of non-invasive methods to assess disease severity. Their recommended approach to the patient with suspected NAFLD is summarized in an algorithm suitable for use in community practice.

The genetic polymorphisms that expedite the development of NAFLD and end-stage liver disease are at the heart of the expert review by Marcin Krawczyk and colleagues. Currently known genes that constitute risk factors for excess fat deposition in the liver are detailed herein. The authors demonstrate the importance of individual genetic risk variants to clinical phenotypes using a visual model called “treeWAS:” this method nicely illustrates the ‘catch-22’ of variants in TM6SF2 that exert opposing effects on the cardiovascular system and the liver. Importantly, the review also highlights the disconnect between the gain in knowledge and the lack of benefit that has been achieved for patients by genetic profiling thus far. The authors conclude by detailing a three-dimensional risk space - constituting genes, environment and time - that can be used to educate and guide clinicians in the conceptualization and management of NAFLD.

Opposing the stability of genetic traits are the gut microbiota - which are critically influenced by a mixture of environment and intrinsic factors. Their contribution to the NAFLD phenotype is more difficult to decipher and complex. Thus, the expert review by Judith Aron-Wisnewsky and colleagues is one highlight of this special issue and the authors succeed in sketching an expert picture of the multidimensional gut-liver axis. While this scientific field is expanding rapidly, the basic concepts of alterations in the gut microbiome ‘organ’ are well captured and related back to the disease phenotype. This holds the potential for both diagnostic and therapeutic approaches and it will not be long until clinical trials implement microbiota signatures to fit therapeutic approaches to appropriate target populations.

The intriguing link between the adipose tissue and the hepatic compartment is explored by Vian Azzu and colleagues. The exposed role of the liver in the metabolism predispose it to the storage of fat. This is far from being a passive overflow mechanism, but rather constitutes a multifaceted interaction of the liver with the adipose tissue. Furthermore, the evolutionary proximity of metabolically active cells, immune cells and blood vessels is highlighted to partly explain the fact that fat deposition in the liver can initiate an immune response in selected patients. This immune response impacts on key elements of metabolism including insulin sensitivity and lipid flux. Thus, the available evidence points to the importance of studying the adipose tissue when exploring the evolution of NAFLD and contemplating treatment. The ‘lean NAFLD’ paradigm is nicely put into the perspective of adipose tissue dysfunction. The authors also emphasize lipid distribution phenotypes, rather than obesity per se, as critical regulators of NAFLD.

The factors that drive hepatic fibrogenesis in NAFLD are placed into perspective by Robert Schwabe and colleagues. They emphasize the critical role of cellular crosstalk in the pathway to fibrosis, which involves multi-directional signals among hepatocytes, immune cells and hepatic stellate cells. The authors highlight new observations implicating TAZ, Notch and hedgehog ligands as hepatocyte-derived mediators that can activate stellate cells: this can occur either directly or indirectly through inflammatory cells. The authors also underscore the importance of efferocytosis, or the ingestion of apoptotic cells by macrophages, as a trigger to fibrosis because of its potential to promote secretion of the fibrogenic cytokine TGFβ. Fibrogenic pathways can come full circle, with stellate cells signaling back to hepatocytes to influence cellular lipid homeostasis. Breaking the cycle of harmful cellular crosstalk in the liver by suppressing TAZ or blocking efferocytosis may prove to be a useful to therapeutic strategy in NAFLD.

The concept that a fatty liver can itself promote extrahepatic manifestations of NAFLD is proposed by Nadine Gehrke and Jörn Schattenberg. These authors underscore that a state of “metabolic inflammation,” fueled by hepatic steatosis, can influence the development of insulin resistance, cardiovascular disease and even neurologic decline. These processes are driven in part by inflammatory signals produced by hepatocytes and hepatic macrophages; others are the consequence of liver-specific alterations in cholesterol metabolism that lead to generalized atherogenesis. In the brain, insulin resistance can drive the accumulation of neurotoxic ceramides that induce cognitive dysfunction. In addition, cerebral endothelial cells and microglia are targets of toxic and inflammatory mediators that cross the blood-brain barrier. This liver-brain connection is provocative; however, on a positive note, there is promising information that physical exercise can avert the neurologic complications associated with NAFLD and insulin resistance.

The influence of circadian rhythms on human biology is a subject of great interest, particularly the ability of circadian “dyssynchrony” to perturb metabolism and promote fatty liver disease. Amir Zarrinpar and colleagues describe the molecular organization of the clock and emphasize how circadian regulation of cell biology within the liver affects hepatic metabolism. They make the important point that the liver does not act in isolation - but rather is influenced by external forces including feeding and even the composition of the gut microbiome, which itself is subject to cyclical variation. Knowledge of the multiple circadian influences on metabolism has led to important translational advances, such as the demonstration that dysmetabolic states including NAFLD can be ameliorated by time-restricted feeding.

Pediatricians Dana Goldner and Joel Lavine remind us that children represent special populations in NAFLD with unique disease manifestations and unique influences during growth and development. They underscore that NAFLD may be preprogrammed during fetal development by maternal diet; at the time of birth, delivery method and breast feeding may be important in view of their influence on gut microbial diversity. There are also important considerations during puberty, as alterations in estrogen and testosterone affect disease risk and may differentially affect boys and girls. Importantly, although children are subject to many of the same genetic and environmental risk factors for NAFLD as adults, their histologic liver injury tends to be periportal rather than pericentral. Whether this feature portends a unique pathophysiology that will require tailored therapy is yet undetermined. In their review the authors discuss the challenges faced by pediatricians in diagnosing and treating a disease that evolves during childhood and adolescence.

Drug development is among the most exciting areas in NAFLD research as of today. After consensus on acceptable endpoints for conditional drug approval was reached, a number of phase 3 clinical trials have been initiated. One of these reported positive results in a preplanned interim analysis after 18 months of treatment, demonstrating that fibrosis regression can be achieved and supporting the concept that NAFLD is a ‘druggable’ disease. From his expert perspective Brent Neuschwander-Tetri details the disease pathways currently being explored in NAFLD and the rationale underlying the development of drugs targeting these pathways. Importantly, he starts out by highlighting that significant effects can also be achieved from lifestyle changes in this indication. Thus, going forward the fine balance between addressing NAFLD by counseling on lifestyle changes while selecting the subgroup of patients that will benefit the most from soon to be expected drugs is currently the ‘holy grail’ of NAFLD management.

Importantly, the development of this special issue coincided with efforts by a consortium of world experts to challenge the accuracy of the term NAFLD as a descriptor. In the final article of the issue this group, represented by Mohammed Eslam, Arun Sanyal and Jacob George, recommend the adoption of a new term to replace NAFLD entitled metabolic (dysfunction) associated fatty liver disease or “MAFLD.” The authors argue that adopting a new nomenclature is timely and necessary to recognize the contribution of dysmetabolism to liver disease in at-risk subjects that may also exhibit hepatic comorbidities such as viral hepatitis or behaviors such as moderate alcohol consumption. They also emphasize that a general term will actively acknowledge disease heterogeneity, for example, across individuals who may be lean or obese. They envision that under the broad umbrella of MAFLD there will be subtypes identified by biomarkers or other means that can be used to stratify risk and tailor specific therapies.

We are deeply indebted to the thought leaders who shared their expertise to create this compendium of articles. Their collective voices provide a clear framework of our understanding of NAFLD in 2020; they also inspire us to move boldly to redefine the disease in the future.

Biographies

Jacquelyn J. Maher

Jörn M. Schattenberg