Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Gunarathne, Lakmie S.; Rajapaksha, Harinda; Shackel, Nicholas; Angus, Peter W; Herath, Chandana B

doi:10.3748/wjg.v26.i40.6111

Cited by 57 publications

(54 citation statements)

References 257 publications

(313 reference statements)

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“…Many hypotheses have been developed regarding the mechanisms, through which statins convey their protective effects against HCC development in CLD. Suggested mechanisms include chemoprevention, inhibition of CLD progression to cirrhosis, and impedance of cirrhosis evolution and decompensation [ 82 ].…”

Section: Clinical Data On the Use Of Statins In Patients With Cldmentioning

confidence: 99%

Statin Use in Patients With Chronic Liver Disease and Cirrhosis: Current Evidence and Future Directions

et al. 2022

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Chronic liver disease (CLD) and its complications constitute a significant cause of mortality and morbidity worldwide. Most deaths are secondary to the decompensation of cirrhosis and evolution of portal hypertension (PHTN). Since disease progression reversal is hardly attainable after decompensated cirrhosis develops, it is essential to intervene early with a therapeutic agent or regimen that could prevent or slow disease evolution. Thus far, there has been no agreed-upon medication to help in the fight against the development of cirrhosis or its decompensation. While early data depicted statins as harmful agents for the liver, current evidence from preclinical and clinical studies suggests that they might have positive impact on CLD. Low-quality evidence supports the fact that statins reduce mortality in CLD. Moderate-quality evidence suggests that statins reduce the risk of hepatic decompensation, variceal bleeding, and mortality, especially among patients with compensated cirrhosis. Combining this data with the long track-record of safety and tolerability of statins and their potential benefits in hepatocellular carcinoma (HCC) risk reduction, hepatologists might soon rely on statins to achieve better outcomes in their CLD and cirrhotic patients without significant additional costs. This review describes the rationale behind the use of statins in patients with CLD and cirrhosis. It sheds light on the current preclinical and clinical studies that reflect beneficial effects of the use of different types and doses of statins in the treatment of patients with different types and stages of CLD and cirrhosis. It also emphasizes the need for designing and developing additional large prospective interventional randomized control trials (RCTs) to better evaluate the association between statin exposure and the risk of fibrosis progression and development of cirrhosis in patients with non-cirrhotic CLDs, the risk of progression of PHTN in patients with cirrhosis, and the mortality rates in patients with cirrhotic or non-cirrhotic CLDs.

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Section: Clinical Data On the Use Of Statins In Patients With Cldmentioning

confidence: 99%

Statin Use in Patients With Chronic Liver Disease and Cirrhosis: Current Evidence and Future Directions

et al. 2022

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“…ACE, angiotensin converting enzyme; ACE2, angiotensin converting enzyme 2; eNOS, endothelial nitric oxide synthase. Adapted from [ 102 ].…”

Section: Figurementioning

confidence: 99%

Update on New Aspects of the Renin-Angiotensin System in Hepatic Fibrosis and Portal Hypertension: Implications for Novel Therapeutic Options

Rajapaksha

Gunarathne

Angus

et al. 2021

JCM

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There is considerable experimental evidence that the renin angiotensin system (RAS) plays a central role in both hepatic fibrogenesis and portal hypertension. Angiotensin converting enzyme (ACE), a key enzyme of the classical RAS, converts angiotensin I (Ang I) to angiotensin II (Ang II), which acts via the Ang II type 1 receptor (AT1R) to stimulate hepatic fibrosis and increase intrahepatic vascular tone and portal pressure. Inhibitors of the classical RAS, drugs which are widely used in clinical practice in patients with hypertension, have been shown to inhibit liver fibrosis in animal models but their efficacy in human liver disease is yet to be tested in adequately powered clinical trials. Small trials in cirrhotic patients have demonstrated that these drugs may lower portal pressure but produce off-target complications such as systemic hypotension and renal failure. More recently, the alternate RAS, comprising its key enzyme, ACE2, the effector peptide angiotensin-(1–7) (Ang-(1–7)) which mediates its effects via the putative receptor Mas (MasR), has also been implicated in the pathogenesis of liver fibrosis and portal hypertension. This system is activated in both preclinical animal models and human chronic liver disease and it is now well established that the alternate RAS counter-regulates many of the deleterious effects of the ACE-dependent classical RAS. Work from our laboratory has demonstrated that liver-specific ACE2 overexpression reduces hepatic fibrosis and liver perfusion pressure without producing off-target effects. In addition, recent studies suggest that the blockers of the receptors of alternate RAS, such as the MasR and Mas related G protein-coupled receptor type-D (MrgD), increase splanchnic vascular resistance in cirrhotic animals, and thus drugs targeting the alternate RAS may be useful in the treatment of portal hypertension. This review outlines the role of the RAS in liver fibrosis and portal hypertension with a special emphasis on the possible new therapeutic approaches targeting the ACE2-driven alternate RAS.

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“…These changes profoundly affect the hepatic vascular tone of the fibrotic liver. However, there is an extrahepatic contributor as well, the splanchnic vascular bed [129]. Several reports showed that elevation in splanchnic blood flow and reduced splanchnic arteriolar resistance lead to chronic elevations in portal pressure and hyperdynamic systemic circulation with high cardiac index and low systemic arterial resistance [120,[130][131][132][133][134][135].…”

Section: Portal Hypertensionmentioning

confidence: 99%

The Space of Disse: The Liver Hub in Health and Disease

Sanz‐Garcia

Fernández‐Iglesias

Gracia‐Sancho

et al. 2021

Livers

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Since it was first described by the German anatomist and histologist, Joseph Hugo Vincenz Disse, the structure and functions of the space of Disse, a thin perisinusoidal area between the endothelial cells and hepatocytes filled with blood plasma, have acquired great importance in liver disease. The space of Disse is home for the hepatic stellate cells (HSCs), the major fibrogenic players in the liver. Quiescent HSCs (qHSCs) store vitamin A, and upon activation they lose their retinol reservoir and become activated. Activated HSCs (aHSCs) are responsible for secretion of extracellular matrix (ECM) into the space of Disse. This early event in hepatic injury is accompanied by loss of the pores—known as fenestrations—of the endothelial cells, triggering loss of balance between the blood flow and the hepatocyte, and underlies the link between fibrosis and organ dysfunction. If the imbalance persists, the expansion of the fibrotic scar followed by the vascularized septae leads to cirrhosis and/or end-stage hepatocellular carcinoma (HCC). Thus, researchers have been focused on finding therapeutic targets that reduce fibrosis. The space of Disse provides the perfect microenvironment for the stem cells niche in the liver and the interchange of nutrients between cells. In the present review article, we focused on the space of Disse, its components and its leading role in liver disease development.

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Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Cited by 57 publications

References 257 publications

Statin Use in Patients With Chronic Liver Disease and Cirrhosis: Current Evidence and Future Directions

Statin Use in Patients With Chronic Liver Disease and Cirrhosis: Current Evidence and Future Directions

Update on New Aspects of the Renin-Angiotensin System in Hepatic Fibrosis and Portal Hypertension: Implications for Novel Therapeutic Options

The Space of Disse: The Liver Hub in Health and Disease

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