Extra-hepatic cancers in metabolic fatty liver syndromes

Abstract

The liver operates an array of vital digestive, metabolic, immunological, and purificatory physiological functions including synthesis of albumin, regulation of glucose and lipid homeostasis, detoxification of ammonia and xenobiotics, choleresis and production of hepatokines and hormones [1]. However, in healthy states, it is not involved in the storage of fatty substrates and, whenever the normal liver threshold is exceeded, accumulated triglycerides will impair whole-body insulin sensitivity, trigger sterile low-grade hepatic metaflammation, and promote the progression of the fibrosing process that will eventually conduce to cirrhosis in a subset of individuals [2,3]. While the histopathological cascade described above was first recognized in the 1800s by distinguished liver pathologists, such as Addison, Rokitansky, Pepper, and Bartolow, until the years 1958-1971 the debate, with the contributions by Zelman and Thaler, mainly focused on such hepato-histopathological changes being indistinguishable irrespective of the inciting triggers: alcohol, obesity, and diabetes [4]. From the perspective of clinical nosography, this finding eventually led to coining the innovative definitions of "nonalcoholic steatohepatitis (NASH)" and "nonalcoholic fatty liver disease (NAFLD)" in the 1980s. "Nonalcoholic" is a composite word that, at least in the spelling used by Ludwig et al., and by Schaffner and Thaler; does not require any hyphens [4] at variance with the use that is sometimes encountered in contemporary literature ("non-alcoholic").To convert a "negative" definition (i.e., nonalcoholic) into a positive diagnosis highlighting the pathogenic (dysmetabolic) origin, while also avoiding stigmatizing alcohol consumption, a panel of international experts have proposed renaming NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD). Although endorsed to an unprecedented extent [5], MAFLD retains some elements of ambiguity and amplifies NAFLD's heterogeneity, therefore creating major implications for research arena and clinical practice [6,7].Compared to the history of NAFLD briefly summarized above, the notions that NAFLD and NAFLD-related metabolic conditions could also be a risk factor for the development of primary liver cancer (PLC) in a limited proportion of individuals are more recent (Table 1) [8-13].While it is logical and somewhat foreseeable that PLC may eventually develop in some individuals with NAFLD, more recent observations substantiate the probably unexpected theory that, further to PLCs, NAFLD

PRO‐C3, liver fibrosis and CKD: The plot thickens

“…12 Interestingly, liver fibrosis is also a strong correlate of extrahepatic features of NAFLD, such as major adverse cardiovascular events, risk of incident diabetes and CKD. 14 On these grounds, given invasiveness, risks of complications, costs and inherent intraand inter-observer variability of findings of liver biopsy, tools to assess liver fibrosis non-invasively are eagerly awaited in as much as they could be leveraged to screen large patient populations as well as for monitoring disease progression and effectiveness of treatment. 3,15 The sequential utilization of non-invasive tests (such as FIB-4 and elastography or others) has rationally been proposed to this end, 15 but it may be difficult to implement in primary care settings globally.…”