Clinical course of non-alcoholic fatty liver disease and the implications for clinical trial design

Noninvasive serum biomarkers for liver fibrosis in NAFLD: current and future

“…47 Also, the risk of death was higher in individuals with FIB-4 >2.67 (HR 3.26; p<0.001). 47 In a different study, it has been shown that ELF ™ predicts clinical outcomes more accurately than liver biopsy. 48 A one-point increase in ELF ™ score was associated with a twofold increase in risk of liver related clinical outcome (defined as liver related death or episode of decompensated cirrhosis e.g.…”

Portal hypertension is a key determinant of the risk for liver-related events in non-alcoholic fatty liver disease

“…To conclude, we need further large-scale studies that define the specific risk for liverrelated events in NAFLD-ACLD patients, similar to the study of Allen AM et al (1) We would like to advocate for studies that include a well-characterised cohort of patients with verified ACLD due to NAFLD, and even more importantly, a detailed characterisation of the severity of PH, best by means of HVPG. The results of these trials will allow for the characterisation and subsequent selection of NAFLD-ACLD patients at particularly high risk of hepatic decompensation for clinical trials with a sufficiently high expected event rate, evading the need to include >500-1000 patients, as suggested by Allen AM et al (1), to be sufficiently powered to detect therapeutically relevant differences(10).…”

“…Hence, the study by Allen AM et al (1) describing the clinical course of 5123 NAFLD patients over a median follow-up time of 6.4 years is a valuable contribution to the field. When drawing conclusions, especially on the expected disease course, it is, however, important to reflect on the specific characteristics of the respective patient cohort from which results have been obtained.…”

“…First, the selection of any patient cohort (and especially of NAFLD aetiology) by using codes/key words may be problematic and prone to selection bias. In their study (1) the authors state that within 20 years after initial NAFLD diagnosis "other liver disease(s)" were diagnosed in 26% of patients. Since fatty liver disease may be multifactorial and can co-exist with other aetiologies, fuelling the current debate on metabolic associated liver disease (MAFLD), NAFLD still could be a concomitant driver of liver disease progression in these patients with other aetiologies.…”

To do one and to get more: Part II. Diabetes and metabolic dysfunction-associated fatty liver diseases

“…13, In brief, MAFLD, characterized by the fat accumulation >5% (by histological examination) or >5.6% (by magnetic resonance imaging (MRI)-derived proton density fat fraction [MRI-PDFF]) of hepatocytes (presence of steatosis) without excessive alcohol consumption or secondary causes of hepatic steatosis, presents a biggest health hazard globally, based on its potential continuous progression to advanced liver fibrosis (liver cirrhosis) and finally the development of hepatocellular carcinoma (HCC), contributing to the heavy economic and social burdens worldwide. [65][66][67]88,[90][91][92][93][94][95][96][97][98][99][100] Pathogenesis of MAFLD, similar to DM, is a result of multiple interactions and/or cross-talks among genetic, epigenetic, environmental and micro-organisms (Fig. 1), including genetic and epigenetic factors (acetyl-CoA carboxylase, adipophilin [adipose differentiation-related protein], apolipoprotein C3, adenosine triphosphate citrate lyase [Acly], calpain 10, carbohydrate response element-binding protein, catalase, ectoenzyme nucleotide pyrophosphate phosphodiesterase 1, Forkhead box protein O1, free fatty acid [FFA] oxidation-related genes such as branched-chain acyl-CoA oxidase, carnitine palmitoyltransferase 1a, cytochrome P450 2E1, cytochrome P4A11, long-chain acyl-CoA dehydrogenase, long-chain L-3-hydroxyacylcoensyme A dehydrogenase alpha, uncoupling protein 2, FFA synthase, glutathione peroxidase [GPX], insulin receptor substrate, patatin like phospholipase domain-containing protein-3, peroxisome proliferator-activated receptor-γ [PPAR-γ], sterol regulatory elementbinding protein, and superoxide dismutase 2 [SOD2]) to result in malfunction of metabolism and dysregulation of immunological system, hormone system and other homeostasis status in human body; gut metabolome and environmental factors, such as drugs, heavy mental, toxins, infection to further augment oxidative stress secondary to unbalance input and output-metabolic dysregulation mediated by production of oxidative stress factors (fibroblast growth factor 21 [FGF 21], thioredoxin, copper-to-zinc SOD2, GPX, Mac-2 binding protein: M2BP, and others) as well as inflammatory factors (CC-chemokine ligand 2, c-Jun-N-terminal kinase, CRP, glycogen synthase kinase 3, interleukin 1-beta, 2, 6 and 8, and tumor necrosis factor-alpha), and formatting reactive oxygen species-reactive oxygen species leading to the increase of superoxide anion radicals to form adducts with cellular nucleophiles, cellular damage, and inflammatory responses as well as the release of a lots of amount of cytokine, adipocytokines (adipokines, adiponectin, apelin, hepcidin leptin, resistin, vaspin, and visfatin), and therefore, IR and MeS develop with subsequently progression to more specific diseases, such as DM, MAFLD, etc.…”