Recent advances in understanding liver fibrosis: bridging basic science and individualized treatment concepts

Abstract

Hepatic fibrosis is characterized by the formation and deposition of excess fibrous connective tissue, leading to progressive architectural tissue remodeling. Irrespective of the underlying noxious trigger, tissue damage induces an inflammatory response involving the local vascular system and the immune system and a systemic mobilization of endocrine and neurological mediators, ultimately leading to the activation of matrix-producing cell populations. Genetic disorders, chronic viral infection, alcohol abuse, autoimmune attacks, metabolic disorders, cholestasis, alterations in bile acid composition or concentration, venous obstruction, and parasite infections are well-established factors that predispose one to hepatic fibrosis. In addition, excess fat and other lipotoxic mediators provoking endoplasmic reticulum stress, alteration of mitochondrial function, oxidative stress, and modifications in the microbiota are associated with non-alcoholic fatty liver disease and, subsequently, the initiation and progression of hepatic fibrosis. Multidisciplinary panels of experts have developed practice guidelines, including recommendations of preferred therapeutic approaches to a specific cause of hepatic disease, stage of fibrosis, or occurring co-morbidities associated with ongoing loss of hepatic function. Here, we summarize the factors leading to liver fibrosis and the current concepts in anti-fibrotic therapies.

Keywords: NASH; collagen.; genetic disorders; hepatitis; liver fibrosis; microbiota; steatosis; therapy; viral infection.

Figure 1.. Pathogenesis of hepatic fibrosis.

Prolonged liver injury results in changes in hepatic architecture and advanced fibrosis. At the cellular level, quiescent hepatic stellate cells (HSCs) become triggered by soluble mediators (chemokines and cytokines) released by liver-resident macrophages (Kupffer cells), infiltrating leukocytes, and other cell types including damaged hepatocytes. Both activated HSCs and transdifferentiated myofibroblasts (MFBs) are positive for α-smooth muscle actin (α-SMA). MFBs are the predominant source of collagen synthesis and deposition. The pool of extracellular matrix (ECM)-producing MFBs is further increased by different cell types such as resident fibroblasts, mesothelial cells, circulating (bone marrow) fibrocytes, epithelial cells, endothelial cells, pericytes, vascular smooth muscle cells, and other specialized cell types that acquire pro-fibrogenic activities and become capable of expressing ECM components. The relevant molecular and cellular mechanisms including epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndoMT), mesothelial-to-mesenchymal transition (MMT), recruitment, activation, proliferation, transdifferentiation, and infiltration are being intensively studied presently. For more details, see , . HBV, hepatitis B virus; HCV, hepatitis C virus.

Figure 2.. Major causes of hepatic fibrosis.

In the liver, genetic alterations, metabolic disorders, cholestasis, viral infections, parasites, drugs, toxins, alcohol leading to alcoholic liver disease (ALD), and a wide variety of other noxious compounds and environmental factors can lead to the initiation and progression of fibrosis. AIH, autoimmune hepatitis; CXCR3, C-X-C motif chemokine receptor 3; HBV, hepatitis B virus; HCV, hepatitis C virus; IL28B, interleukin 28B; NASH, non-alcoholic steatohepatitis; PNPLA3, patatin-like phospholipase domain-containing protein 3; RNF7, ring finger protein 7; TGF-β, transforming growth factor-β.

Figure 3.. Strategies to induce resolution of hepatic fibrosis.

Ongoing hepatic fibrosis can be haltered or resolved by specific therapies, eradication or dietary restriction of the pathogenic cause, or lifestyle and dietary interventions. In addition, several neglected features of lifestyle such as physical exercise, sun exposure, vitamin supplementation, and improved sleep duration and rhythm have been shown to be beneficial in the management of hepatic fibrosis. For more detailed explanations, see text. ACC, acetyl-CoA carboxylase; ACE, angiotensin-converting enzyme; ALD, alcoholic liver disease; ASK1, apoptosis signal-regulating kinase 1; CCL2, C-C motif chemokine ligand 2; CCR2/CCR5, C-C motif chemokine receptor 2/5; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; LOXL2, lysyl oxidase-like 2; NASH, non-alcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; TGR5, G-protein-coupled membrane receptor 5; THR-β, thyroid hormone receptor-β; TIPS, transjugular intrahepatic portosystemic shunt.