The Liver: The Body’s Metabolic Factory

Non-communicable diseases (NCD) before the COVID-19 pandemic were among the most significant diseases affecting global health. These include cardiovascular diseases, diabetes mellitus, cancer, chronic respiratory diseases and neurological diseases. Their prevalence was in part associated with increased life expectancy and with a series of risk factors, including overweight and obesity, smoking, physical inactivity, excessive alcohol intake and limited access to general and preventive healthcare. 

During the pandemic, people affected by NCD represented one of the highest risk population groups for morbidity and mortality. Addressing the relationship between both is now the interest of multiple research sites worldwide. Implicit is the fact that COVID-19 resulted in a major disruption of screening, treatment and follow-up of patients with NCD. As time goes by, we increasingly are witnessing the appearance of long COVID or postCOVID-19 whose pathophysiology remains an enigma and represents a big challenge. As both NCD and COVID-19 share factors associated with worse outcomes, the suspicion of an underlying metabolic disorder has grown more certain. Chronic inflammation and immune cell activation are pathological processes in both circumstances; the role of adipocytes, macrophages and natural killer cells has been documented in addition to others, such as insulin resistance, fatty liver disease or metabolic syndrome. 

The liver is one of the most outstanding organs involved in metabolism in general. It is vital to maintain the homeostasis of organisms and, therefore, contributes to survival. In mammals, liver regeneration can be understood as an adaptive response to harm. A number of evolutionary safeguards allow it to continue to perform its complex functions despite significant injury. For example, following a partial hepatectomy involved in human liver transplantation, an accepted treatment for end-stage liver disease, within two weeks the donated liver regenerates to a size equivalent to the original mass while the remaining liver also returns to its normal size within six months  

The numerous signaling pathways involved in liver regeneration are complex and interconnected. They include cytokines, growth factors, and a metabolic network. Immediately following a partial hepatectomy, greater than 100 early genes are activated by transcription factors that are latent in the quiescent liver. 

Amazingly once the liver regenerates to its normal size, the regenerative process terminates and the liver recuperates its normal metabolic function, which includes metabolizing lipids, synthesizing proteins, production of bile, metabolism of carbohydrates, elimination of toxic metabolites, synthesis of coagulation factors, macro and micronutrient metabolism, blood volume regulation, immune system support, endocrine control of growth signaling pathways among others. The liver is, therefore, a critical hub for numerous physiological processes. 

Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide, related to the increased epidemic proportions of obesity and diabetes worldwide. Its prevalence has increased to more than 30% of adults in developed countries and its incidence is still rising. The majority of patients with NAFLD have simple steatosis, mostly a benign condition, but in up to one-third of patients, NAFLD progresses to its more severe form, nonalcoholic steatohepatitis (NASH), that is characterized by liver inflammation and injury that can lead to development of liver fibrosis and hepatocellular cancer. NAFLD is considered the hepatic manifestation of metabolic syndrome. However, the liver is not only a passive target, on the contrary it becomes involved in the pathogenesis of the metabolic syndrome and its complications. Conversely, pathophysiological changes in other sites such as in the adipose tissue, the intestinal barrier or the immune system have been identified as triggers and promoters of NAFLD progression. Innumerable reports have so far centered on the development of non-alcoholic fatty liver diseases (NAFLD) or alcohol related liver disease but more recently the recommendation has been proposed to call it metabolic associated liver disease (MAFLD). This opens the door to efforts to identify subsets of phenotype of metabolic liver disease that could provide new pathways to approach the understanding of metabolic risk factors in the development of a myriad of pathologies and the opportunity to explore the interrelation between age, sex, ethnicity and diet, with genetics and epigenetics and metabolic health which in the end could provide information to understand the variable response to treatments. The proposal is that the diagnosis of MAFLD could be established in the presence of metabolic dysfunction. 

As the liver performs over 500 chemical functions, it is no surprise it has been often referred to as the body’s metabolic factory. As we are witnessing the fifth Industrial Revolution focused on the cooperation of man, machine and artificial intelligence, we can only be astonished by and thankful for the efficiency of the liver. Symbolic accounts of the liver’s functions have been influenced by scientific advances throughout the ages, and one of the most inspiring is that of the Chilean Nobel Laureate poet Pablo Neruda in his “Ode to the Liver” when he says that the soaring of his ode is born on the invisible machinery, that flies from is tireless confined mill, delicate, powerful entrail, ever alive and dark.