Development and Regression of Cirrhosis

Liver cirrhosis is the ultimate consequence of the wound healing reaction subsequent to a chronic injury, which leads to a complete derangement of the normal hepatic lobular and vascular architecture. Cirrhosis is characterized by patterns of evolution depending on the causative agent and a series of complex underlining mechanisms in which neo-angiogenesis and necro-inflammation play a key role. The importance of the different cell types involved and of the extracellular matrix composition as well as the role of innate immunity, bacterial translocation and oxidative stress are also emerging. A variable degree of regression of fibrosis and even cirrhosis has been described, in experimental models, after suspension of the liver disease causative agent. As some individual features influence the rate of fibrosis progression, genetic and epigenetic factors are likely to influence fibrosis regression. Key Messages: There is increasing awareness that cirrhosis is not a static condition but a dynamic process. Current semi-quantitative scores and clinical classifications are inaccurate and unable to identify the different phases of evolution of the advanced stages of chronic liver diseases (CLDs). The increasing availability of effective etiology-driven therapeutic options for CLDs makes reversion of cirrhosis a more possible prospective. However, the removal of the causing agent, depending on the stage of the disease, does not necessarily eliminate the risk of disease progression, decompensation and development of hepatocellular carcinoma. Also, the non-invasive markers currently validated for the assessment of fibrosis are not suitable for an effective evaluation of fibrosis regression. Conclusions: There is a critical need of a system that would be able to more accurately describe the dynamic development of cirrhosis and the impact of tissue fibrosis, neo-angiogenesis, necro-inflammation and attempted regeneration on its evolution. Effective treatment of CLD can lead to a variable degree of fibrosis regression. New markers able to evaluate this process will need to be detected and validated

The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. Despite its high prevalence, only a small minority of affected patients develops inflammation and subsequently fibrosis and chronic liver disease, while most of them only exhibit simple steatosis. In this context, the full understanding of the mechanisms underlying the development of NAFLD and non-alcoholic steatohepatitis (NASH) is of extreme importance; despite advances in this field, knowledge on the pathogenesis of NAFLD is still incomplete. The 'two-hit' hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD. The "multiple hit" hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors. In this article, we review the factors that form this hypothesis

Utility of ElastPQ point-shear wave elastography in the work-up of patients with primary sclerosing cholangitis

Background & Aims: Liver stiffness measurement (LSM) and spleen stiffness measurement (SSM) have been shown to be useful tools for assessing the risk of fibrosis and portal hypertension, respectively. However, data on the accuracy of LSM and SSM measured by point-shear wave elastography (pSWE) in patients affected by primary sclerosing cholangitis (PSC) are still lacking. Thus, we aimed to prospectively assess their performance in a cohort of patients with PSC. Methods: We determined the correlation between LSM assessed by a pSWE technique (ElastPQ) and by FibroScan-transient elastography (F-TE). Furthermore, we used receiver-operating characteristic curves and area under the curves (AUROC) to evaluate the performance of LSM by ElastPQ for the staging of fibrosis, using F-TE as a reference standard, and the performance of LSM and SSM by ElastPQ in predicting the presence of oesophageal varices (OVs). Results: One hundred and fifty-two patients with PSC (93 males [61.2%], mean age 46 ± 16 years) were prospectively recruited. ElastPQ and F-TE LSMs were available for all patients, while ElastPQ SSM was available in 109 (72%) patients of whom 35 underwent upper gastrointestinal endoscopy within 1 year of the ultrasound assessment. ElastPQ LSM showed an excellent correlation with F-TE (p <0.001, Spearman's 0.93; Lin's 0.86) and a good diagnostic accuracy for fibrosis staging along all stages of liver fibrosis (AUROCs 0.96, 0.97, 0.97 and 0.99 for fibrosis stages F≥1, F≥2, F≥3 and F=4, respectively), using F-TE as a surrogate of histological fibrosis. ElastPQ SSM showed a good diagnostic performance in predicting the presence of OVs at endoscopy. Conclusions: LSM and SSM by ElastPQ can be used as accurate tools for liver fibrosis risk assessment and fibrosis staging, as well as for predicting the presence of OVs in the work-up of patients with PSC. Impact and implications: Liver and spleen stiffness measurement (LSM and SSM, respectively) by ElastPQ point-shear wave elastography in patients with primary sclerosing cholangitis represent reliable and reproducible tools for non-invasively staging the severity of liver disease and stratifying patients according to their risk of developing liver-related outcomes. In particular, LSM shows good accuracy for staging liver fibrosis and therefore detecting those patients at high risk of having compensated advanced chronic liver disease who require close monitoring. SSM seems to be promising to detect the risk of portal hypertension and therefore of oesophageal varices, enabling the triaging of patients who really need to undergo a screening endoscopy

Pathophysiology of liver fibrosis and the methodological barriers to the development of anti-fibrogenic agents

Liver fibrosis and cirrhosis resulting from long-standing liver damage represents a major health care burden worldwide. To date, there is no anti-fibrogenic agent available, making liver transplantation the only curative treatment for decompensated cirrhotic liver disease. Liver fibrosis can result from different underlying chronic liver disease, such as chronic viral infection, excessive alcohol consumption, fatty liver disease or autoimmune liver diseases. It is becoming increasingly recognised that as a result from different pathogenic mechanisms liver fibrosis must be considered as many different diseases for which individual treatment strategies need to be developed. Moreover, the pathogenic changes of both liver architecture and vascularisation in cirrhotic livers, as well as the lack of "true-to-life" in vitro models have impeded the development of an effective anti-fibrogenic drug. Thus, in order to identify an efficient anti-fibrogenic compound, novel in-vitro models mimicking the interplay between pro-fibrogenic cell populations, immune cells and, importantly, the extracellular matrix need to be developed

Pathogenesis of biliary fibrosis

Chronic cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, and, ultimately, to the development of cirrhosis. However, the precise relationship between cholestasis, in its broad meaning, and liver tissue fibrosis is still poorly defined. Fibrogenesis is currently viewed as a dynamic process that appears strictly related to the extent and duration of parenchymal injury. This relationship is clearly evident in the presence of reiterative hepatocellular necrosis due to viral infection or alcohol abuse. It appears that “pure” intralobular intrahepatic cholestasis secondary to biliary secretory failure of the hepatocyte, in absence of hepatocellular damage, lobular inflammation and bile duct damage and/or proliferation, is not associated with marked and/or progressive liver tissue fibrosis. In contrast, marked and progressive liver tissue fibrosis always follows liver diseases characterized by chronic inflammatory bile duct damage as seen in PBC and PSC or chronic mechanical obstruction of the biliary tree. Overall, the fibrogenic process in these clinical conditions appears to be related to a more complex interaction between immune/inflammatory mechanisms, cytokine networks and the derangement of the homeostasis between epithelial and mesenchymal cells. The elucidation of these mechanisms is indeed crucial for the identification of potential diagnostic and therapeutic targets