Liver cirrhosis

Abstract

Cirrhosis is defined as the histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury, which leads to portal hypertension and end-stage liver disease. Recent advances in the understanding of the natural history and pathophysiology of cirrhosis, and in treatment of its complications, have resulted in improved management, quality of life, and life expectancy of patients. Liver transplantation remains the only curative option for a selected group of patients, but pharmacological treatments that can halt progression to decompensated cirrhosis or even reverse cirrhosis are currently being developed. This Seminar focuses on the diagnosis, complications, and management of cirrhosis, and new clinical and scientific developments.

Fig.1. Vascular and architectural alterations in cirrhosis

Mesenteric blood flows via the portal vein and the hepatic artery that extend branches into terminal portal tracts. A, normal liver: Terminal portal tract blood runs through the hepatic sinusoids where fenestrated sinusoidal endothelium which rest on loose connective tissue (space of Disse’) allow for extensive metabolic exchange with the lobular hepatocytes; sinusoidal blood is collected by terminal hepatic venules which disembogue into one of the 3 hepatic veins and finally the caval vein. B, cirrhosis: Activated myofibroblasts that derive from perisinusoidal hepatic stellate cells and portal or central vein fibroblasts proliferate and produce excess extracellular matrix (ECM). This leads to fibrous portal tract expansion, central vein fibrosis and capillarization of the sinusoids, characterized by loss of endothelial fenestrations, congestion of the space of Disse’ with ECM, and separation/encasement of perisinusoidal hepatocyte islands from sinusoidal blood flow by collagenous septa. Blood is directly shunted from terminal portal veins and arteries to central veins, with consequent (intrahepatic) portal hypertension and compromised liver synthetic function.

Fig.2. Initiation and maintenance of fibrogenesis

With continuous injury, primarily to hepatocytes or bile duct epithelia, and / or mechanical stress the normally quiescent hepatic stellate cells and portal/perivenular fibroblasts undergo activation and transdifferentiation to myofibroblasts. These myofibroblasts produce excessive amounts of collagens, downregulate certain matrix metalloproteinases (MMPs) and show an enhanced expression of the physiological inhibitors of the MMPs (TIMP-1 and -2). TIMP-1 can also promote myofibroblast proliferation and inhibit their apoptosis.

Fig.3. Utilization of biomarkers for staging liver fibrosis and diagnosis of cirrhosis

Fig.4. Antifibrotic approaches and candidates for combination therapy

An important principle is inhibition of TGFβ, either by blocking molecules that induce its proteolytic activation from latent TGFβ, or by its direct inhibition. However, this has to be a targeted approach, since complete abrogation of TGFβ leads to cellular dedifferentiation and severe (intestinal) inflammation. AT, angiotensin; AT1R, angiotensin 1 receptor; CTGF, connective tissue growth factor; ET-1, endothelin-1; ET_AR, endothelin A receptor; FASL, FAS ligand; MMF, mycophenolate mofetil; MMP, matrix metalloproteinase; NGF, nerve growth factor; PDGF, platelet derived growth factor; TGF, transforming growth factor; tPA tissue plasminogen activator; PPAR, peroxisome proliferator activated receptor.