Pathophysiology and a Rational Basis of Therapy

Abstract

Portal hypertension is a common complication of chronic liver disease. Its relevance comes from the fact that it determines most complications leading to death or liver transplantation in patients with cirrhosis of the liver: bleeding from esophageal or gastric varices, ascites and renal dysfunction, sepsis and hepatic encephalopathy. Portal hypertension results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (1) distortion of the liver vascular architecture due to the liver disease causing structural abnormalities (nodule formation, remodeling of liver sinusoids, fibrosis, angiogenesis and vascular occlusion), and (2) increased hepatic vascular tone due to sinusoidal endothelial dysfunction, which results in a defective production of endogenous vasodilators, mainly nitric oxide (NO), and increased production of vasoconstrictors (thromboxane A₂, cysteinyl leukotrienes, angiotensin II, endothelins and an activated adrenergic system). Hepatic endothelial dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress, and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSECs) that become proliferative, prothrombotic, proinflammatory and vasoconstrictor. The cross-talk between LSECs and hepatic stellate cells (HSCs) induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis, which further increase the hepatic vascular resistance and worsen liver failure by interfering with the blood perfusion of the liver parenchyma. An additional factor further worsening portal hypertension is an increased blood flow through the portal system due to splanchnic vasodilatation. This is an adaptive response to decreased effective hepatocyte perfusion, and is maximal once portal pressure has increased sufficiently to promote the development of intrahepatic shunts and portal-systemic collaterals, including varices, through which portal blood flow bypasses the liver. In human portal hypertension collateralization and hyperdynamic circulation start at a portal pressure gradient >10 mm Hg. Rational therapy for portal hypertension aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments (the best example being the direct-acting antivirals for hepatitis C viral infection), while architectural disruption and fibrosis can be ameliorated by a variety of antifibrotic drugs and antiangiogenic strategies. Several drugs in this category are currently under investigation in phase II-III randomized controlled trials. Sinusoidal endothelial dysfunction is ameliorated by statins as well as by other drugs increasing NO availability. It is of note that simvastatin has already been proven to b...

Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats

“…Several studies have demonstrated that celecoxib could efficiently ameliorate portal hypertension and fibrosis in several animal models [ 6 , 12 , 13 , 34 ]. Octreotide is indicated for the management of bleeding from gastroesophageal varices in patients with cirrhosis [ 14 ]. The regime to combine celecoxib with octreotide was firstly investigated in the rat model with cirrhotic portal hypertension in our study.…”

“…Moreover, such effect is related to its inhibition of intrahepatic angiogenesis and epithelial-to-mesenchymal transition of hepatocytes [ 12 , 13 ]. Somatostatin (SST) and its analogue octreotide are widely used for the management of bleeding from gastroesophageal varices in patients with cirrhosis [ 14 ]. It is notable that octreotide could inhibit angiogenesis in HCC and in the early stage of portal hypertension induced by partial portal vein ligation [ 15 , 16 ].…”

Systemic hemodynamics in advanced cirrhosis: Concerns during perioperative period of liver transplantation

“…All transfusion management plans should be handled with great caution, and transplant physicians should very carefully evaluate the effects of increases or decreases of transfusions [60][61][62] . A response time lag due to endothelial injury and permeant breakdown should be considered in LC recipients with long-term PH [63][64][65] . Adequate hydration is also required; dehydration should be avoided because of these patients' peculiar hemodynamics.…”

“…Peculiar hemodynamics in advanced cirrhosis permeant breakdown, and systemic arterial pressure may be effected even by body motion [63][64][65] . Diuretics (e.g., furosemide and potassium-conserving diuretics) and a water-clearance mediator (e.g., tolvaptan) are available [71] .…”

Restructuring of the vascular bed in response to hemodynamic disturbances in portal hypertension

“…The cause of these disorders may be the flow of vasodilator substances ( e.g ., glucagon, endocannabinoid, atrial natriuretic peptide, bacterial endotoxin) through the network of portosystemic shunts, as well as increased production of topical vasodilators by endothelium, such as NO, carbon monoxide, PGI2, endothelium-derived hyperpolarizing factor, adrenomedullin, hydrogen sulfide. Furthermore, in spite of increased circulating levels of endogenous vasoconstrictors (noradrenaline, ET-1, angiotensin II), vascular sensitivity to them is significantly reduced[41]. …”