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.

FIGRE 1

Different patterns of fibrotic evolution in different chronic liver diseases. The three major patterns of fibrotic evolution are illustrated. The “postnecrotic” pattern is typical of chronic viral hepatitis and is mainly characterized by portocentral evolution with early involvement of the centrilobular vein. Sinusoidal arterialization and neoangiogenesis are also typical of this pattern. Fibrogenesis originating in lobular zone 3 (“pericentral fibrosis”) is a main feature of chronic alcoholic hepatitis and NASH. Here, the main feature is the capillarization of sinusoids in zone 3 that progressively becomes panlobular. Biliary fibrosis, a key feature of primary biliary cholangitis and primary sclerosing cholangitis, evolves mainly portal to portal with progressive worsening of cholestasis. CLV, centrilobular vein

FIGURE 2

Current unmet needs in hepatic fibrosis from basic to translational to clinical perspectives. Shown are the unmet needs and current gaps in hepatic fibrosis outlined in this review, surrounding an image of a cirrhotic liver within which are the cellular changes on the left and the appearance of fibrosis on the right. These unmet needs are displayed along the continuum from basic through translational to clinical research