Cirrhosis, and its main complication portal hypertension (PH), represent a serious leading cause of mortality worldwide, accounting for more than 170,000 deaths per year in Europe. The primary factor contributing to the development of PH is a progressive increase in the hepatic vascular resistance due to both architectural distortions of liver parenchyma and to the deregulation of sinusoidal cells phenotype. In addition, an increase in portal blood flow and formation of portal-systemic collaterals perpetuate and further aggravate this syndrome.
During the last decades, continuous research has focused on developing therapeutic options to reduce PH in patients with cirrhosis with the aim to improve their prognosis. However, until now nonselective beta-blockers (propranolol, nadolol, and carvedilol) are the only drugs that have been shown to be clinically effective in patients with cirrhosis.
In the current issue of Hepatology, Verbeke et al. evaluate the effects of the administration of obeticholic acid (OCA), an agonist of the farnesoid-X-receptor (FXR), on PH in two murine models of experimental liver cirrhosis (bile duct ligation [BDL] and thioacetamide [TAA] intoxication). FXR, a bile-acid-responsive transcription factor expressed in the liver, orchestrates a multiplicity of signaling pathways, including those related to bile acid homeostasis, carbohydrates and lipids metabolism, and vasoactive systems, among others.[5-7] In addition, it has been suggested, although controversial, that FXR modulates liver fibrosis.[8, 9] The study published herein demonstrates a reduced FXR expression in the two murine models of cirrhosis. More important, acute (24 hours) and semichronic (10 days) systemic administration of OCA effectively activates FXR, as shown by the increase in its downstream effector small heterodimer partner (SHP), and produces a significant reduction in portal pressure in both models of cirrhosis. Indeed, cirrhotic rats receiving OCA had a mean portal pressure 15-21% lower than their counterpart cirrhotic rats treated with vehicle. This is not an irrelevant reduction if we appreciate that reductions of portal pressure over 10%, after acute propranolol administration, are associated with an improved outcome.
Using the in situ liver perfusion system, where portal perfusion pressure is monitored under constant flow conditions, the authors demonstrate that cirrhotic rats receiving OCA exhibit lower ex vivo hepatic vascular resistance than those treated with vehicle, suggesting that OCA reduces portal pressure by reducing intrahepatic vascular resistance. Unfortunately, in vivo portal blood flow was not measured and therefore a possible additional action of OCA on it cannot be discarded.
Improvement in the hepatic vasodilator response to acetylcholine, together with the increased hepatic endothelial nitric oxide synthase (eNOS) activation produced by acute OA administration, shows that in this setting OCA works by modulating intrahepatic vascular tone. Importantly, cirrhotic animals receiving OCA had similar mean arterial pressure as those receiving vehicle, suggesting that the effect of OCA on vascular tone is hepatic-selective and does not extend to the systemic circulation. The lack of systemic effects of OCA is of special relevance when considering a potential treatment for patients with cirrhosis that are often hypotensive and in whom a further reduction in arterial pressure promotes the development of clinical decompensations.
Whether OCA treatment is also able to influence the architectural component of the increased intrahepatic vascular resistance after long-term treatment is not solved by the present study. Although the authors treated a group of rats for 10 days with OCA, they did not evaluate whether these rats exhibited changes in liver fibrosis. Interestingly, a study in patients with nonalcoholic steatohepatitis (NASH) treated with OCA for 6 weeks did not show changes in noninvasive markers of fibrosis such as ELF. Ongoing phase 2 studies in NASH patients receiving OCA for 72 weeks with liver biopsies analysis (clinicaltrials.gov/: NCT01265498), together with a phase 3 study evaluating 1-year OCA administration to patients with primary biliary cirrhosis (NCT01473524), will help to clarify whether or not OCA has an effect on liver fibrosis.
The authors elegantly demonstrate that eNOS activation due to OA occurs through different molecular mechanisms in the BDL model (increased degradation of the eNOS inhibitor ADMA) than in the TAA model (down-regulation of the eNOS inhibitor Rho kinase), highlighting the importance of using more than a single animal model of cirrhosis to solidly demonstrate the effects of a determined therapeutic strategy. Additionally, reproducibility of the beneficial effects of OCA in two experimental models of cirrhosis increases the chances, but of course do not assure, that the effects could also be observed when applied to patients with cirrhosis.
Finally, it is well known that one of the most important complications of PH is the development of spontaneous bacterial peritonitis derived from an increased degree of bacterial translocation. Considering that it has been described that FXR activation markedly improves the intestinal barrier function and reduces bacterial translocation in inflammatory bowel disease, it would be very interesting to evaluate the effects of FXR activation on bacterial translocation in experimental models of liver cirrhosis.
In conclusion, the study by Verbeke et al. provides a rationale to extend the current evaluation of OCA in patients with NASH, and also to more severe forms of liver diseases such as in patients with cirrhosis and PH. If the effect of OCA on reducing PH, without the deleterious effects on arterial pressure, is confirmed, OCA may become a very interesting drug to be tested in clinical settings.
Jordi Gracia-Sancho, Ph.D.,
Virginia Hernández-Gea, M.D., Ph.D.,
and Juan Carlos Garcia-Pagán, M.D., Ph.D.
Barcelona Hepatic Hemodynamic Laboratory
Liver Unit, Hospital Clínic
Institut d'Investigacions Biomèdiques August
Pi i Sunyer (IDIBAPS) and Centro de
Investigación Biomédica en red de enfermedades
hepáticas y digestivas (CIBERehd)