Hepatic fibrosis 2022: Unmet needs and a blueprint for the future

Abstract

Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to the expectation of effective antifibrotic drugs, yet none has been approved. Thus, an assessment of the field is timely, to clarify priorities and accelerate progress. Here, we highlight the successes to date but, more importantly, identify gaps and unmet needs, both experimentally and clinically. These include the need to better define cell-cell interactions and etiology-specific elements of fibrogenesis and their link to disease-specific drivers of portal hypertension. Success in treating viral hepatitis has revealed the remarkable capacity of the liver to degrade scar in reversing fibrosis, yet we know little of the mechanisms underlying this response. Thus, there is an exigent need to clarify the cellular and molecular mechanisms of fibrosis regression in order for therapeutics to mimic the liver's endogenous capacity. Better refined and more predictive in vitro and animal models will hasten drug development. From a clinical perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate to supplant biopsy. More urgently, digital pathology methods that leverage machine learning and artificial intelligence must be validated in order to capture more prognostic information from liver biopsies and better quantify the response to therapies. For more refined treatment of NASH, orthogonal approaches that integrate genetic, clinical, and pathological data sets may yield treatments for specific subphenotypes of the disease.Collectively, these and other advances will strengthen and streamline clinical trials and better link histologic responses to clinical outcomes.

Safety, tolerability, and anti-fibrotic efficacy of the CBP/β-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis: An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study

“…Instances of non-alcoholic steatohepatitis (NASH)-induced liver fibrosis and cirrhosis have recently increased, and several relevant clinical trials have been conducted mainly in Europe and the United States, although many have been discontinued in the middle of development. 7 , 8 , 9 One reason is the use of pathological diagnosis using liver biopsy as a method to confirm the anti-fibrotic therapeutic effect. 7 Although long-standing problems associated with sampling error have been noted, it is suggested that long time periods are required to observe the effect of fibre reduction due to the strength of the connections between fibres that have progressed to cirrhosis.…”

“… 7 , 8 , 9 One reason is the use of pathological diagnosis using liver biopsy as a method to confirm the anti-fibrotic therapeutic effect. 7 Although long-standing problems associated with sampling error have been noted, it is suggested that long time periods are required to observe the effect of fibre reduction due to the strength of the connections between fibres that have progressed to cirrhosis. Recently, there have been more studies on pre-stage fibrosis (F2-3) than on liver cirrhosis.…”

Fibrosis resolution in the mouse liver: role of Mmp12 and potential role of Calpain 1/2

“…Although accumulation of collagen ECM is the de facto definition of fibrosis, the changes to the hepatic ECM that happen during both processes are much diverse than those that happen to collagen (9). Likewise, although it is understood that hepatic fibrosis resolution involves more than simple clearance of collagen ECM, the process and its mediators are incompletely understood, at best (38).…”

“…As mentioned in the Introduction, collagenous ECM accumulation has been the major focus in the field of hepatic fibrosis (2). Likewise, proteases involved in resolution of collagenous ECM (e.g., MMP2 and MMP9) have also received a sizeable amount of attention (38). Once the technical limitations to identifying peptide fragments of degraded proteins informatically was overcome (42, 43), the fragment sequence and putative cleavage site may yield new information on proteases involved.…”

Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion

“…Because sustained fibrosis leads to the development of end-stage cirrhosis and generates a microenvironment favorable to the development of primary liver cancer [ 1 ], early-stage treatment of liver fibrosis is essential. To date, although some antifibrotic agents have reached clinical trials, effective therapy for fibrosis and cirrhosis in clinical practice remains an unmet medical need [ 2 ].…”