Sage Journals: Discover world-class research

Abstract

Portal hypertension represents one of the major clinical consequences of chronic liver disease, having a deep impact on patients’ prognosis and survival. Its pathophysiology defines a pathological increase in the intrahepatic vascular resistance as the primary factor in its development, being subsequently aggravated by a paradoxical increase in portal blood inflow. Although extensive preclinical and clinical research in the field has been developed in recent decades, no effective treatment targeting its primary mechanism has been defined. The present review critically summarizes the current knowledge in portal hypertension therapeutics, focusing on those strategies driven by the disease pathophysiology and underlying cellular mechanisms.

Keywords

cirrhosis hepatic hemodynamic HVPG portal pressure sinusoid

Introduction

Advanced chronic liver disease (CLD) represents the fourth cause of death due to noncommunicable diseases worldwide. Its high mortality is mainly due to long-time asymptomatic stages during disease progression and, thus, is diagnosed after appearance of portal hypertension (PH) and its clinical complications such as hepatic encephalopathy, variceal hemorrhage or ascites. In fact, PH is the major driver of the complications of CLD, the measurement of hepatic venous pressure gradient (HVPG) being a predictor of the risk of clinical decompensation and survival in compensated cirrhotic patients.^1,2

Clinically significant PH is defined as an HVPG of 10 mmHg or greater and depends on changes in portal blood flow or in intrahepatic vascular resistance (IHVR). During cirrhosis development, elevation in IHVR due to deregulation of hepatic cells and liver fibrosis is the primary factor involved in increasing portal pressure (PP) leading to secondary splanchnic vasodilation and extrahepatic shunt formation, which further aggravate PH and liver dysfunction. Notably, current treatments do not target the main underlying mechanism, but consist in extrahepatic vasoconstrictors [i.e. nonselective beta blockers (NSBB) and somatostatin] aimed at ameliorating PH by reducing the hyperdynamic circulation, or in strategies focused on the prevention of PH-derived complications such as infections or encephalopathy. In the specific case of NSBB, it should be noted that carvedilol may also exert intrahepatic vasodilatation due to its anti-α1-adrenergic properties.³ Despite the extended use of these drugs as the most effective treatment for PH, a recent analysis based on over 100,000 cases showed that 30-day mortality following a decompensation in cirrhosis remains equal, or even higher, than that observed 10 years ago,⁴ strongly suggesting there is a need for new therapeutic approaches for PH and CLD.

In this review we summarize the potential therapeutic strategies for the treatment of PH, which importantly derive from preclinical knowledge and mainly target the increased IHVR. These approaches consist of pharmacological, cell-derived or lifestyle interventions, as shown below.

Vasoprotective strategies

CLD is characterized by persistent injury of the liver due to different etiologies, including alcoholic and nonalcoholic steatohepatitis (NASH) or viral infections. This in turn leads to alterations of the hepatic microvasculature, which in combination with fibrosis constitute the main components of increased IHVR. This scenario of vascular alterations has led to the assessment of different vasoprotective strategies for the treatment of intrahepatic-derived PH, mainly vasomodulators, anticoagulants and antiangiogenic approaches.

Vasomodulators

One of the causes of the abovementioned microvascular alterations during CLD is a shift/alteration in the synthesis of vasoactive molecules in the liver, where vasoconstrictors prevail over vasodilators. Thus, several vasomodulator strategies aimed at enhancing intrahepatic vasodilation and normalizing excessive vasoconstriction have been recently proposed (Figure 1).

Figure 1.

Schematic representation of different therapeutic approaches for portal hypertension focused on their liver vasomodulation effect.

Inhibition of vasoconstriction

One of the most potent vasoconstrictors that contributes to microvascular dysfunction in CLD is endothelin. This molecule is synthesized by the activated endothelium and acts as a ligand for the endothelin receptors (ET) on hepatic stellate cells (HSCs), which are the final effectors of vasoconstriction. Indeed, the use of antagonists targeting ET (either ET_A, ET_B or both) showed improvements in the hepatic sinusoid and in liver fibrosis in preclinical models^5,6 and decreased PP in a small clinical study.⁷ However, its possible beneficial effects were not further validated in human randomized-controlled trials (RCTs).^8,9 Currently ongoing human RCTs evaluating the unspecific antagonist macitentan¹⁰ and ambrisentan¹¹ will provide essential information to support or discard this therapeutic strategy in cirrhosis and PH.

Urotensin is another vasoconstrictor playing a role in PH, known to correlate with HVPG levels.¹² Similar to ET, blockage of the urotensin II receptor with the antagonist palosuran decreases PP in experimental models.¹³ Nevertheless, there are no current studies on cirrhotic patients in order to validate the translatability of these results to the bedside.

Eicosanoids represent another important family of vasoconstrictors derived from the conversion of arachidonic acid. Indeed, cyclooxygenase (COX)-derived prostanoids (a subclass of eicosanoids) are overexpressed in the cirrhotic liver.^14,15 In this regard, several drugs have been used to chronically inhibit either their synthesis (i.e. by COX inhibition with nitroflurbiprofen¹⁶ or celecoxib^17,18) or to block their receptor (e.g. thromboxane A2 receptor with terutroban¹⁹). Although these strategies decreased PP in preclinical models of cirrhosis, there is only one ongoing RCT with the thromboxane receptor antagonist ifetroban.²⁰ Similar strategies aimed at reducing arachidonic acid metabolites focused on inhibiting epoxygenases using MS-PPOH²¹ and cysteinyl leukotrienes with montelukast.²²

In addition to the increased synthesis of vasoconstrictors, the cirrhotic liver is also hypersensitive to these molecules. Thus, research aimed to inhibit the effect of not only hepatic vasoconstrictors, but also systemic ones. In this regard, the renin–angiotensin–aldosterone (RAA) system is a hormone system that controls blood pressure and fluid balance, playing also an important role regulating hepatic hemodynamics. Importantly, angiotensin II is a potent vasoconstrictor peptide with hepatic effects that favors the development of PH.²³ Several strategies have been developed to reduce its effects on the liver: angiotensin-converting-enzyme inhibitors (captopril) and angiotensin receptor blockers (losartan, candesartan, irbesartan) have been tested in preclinical and clinical settings and showed beneficial effects on reducing PH but mainly in compensated patients with Child A cirrhosis.²⁴ Given the potential of these drugs, some strategies aimed at focusing on the RAA system downstream pathway. Indeed, the Janus kinase inhibitor AG490 showed a PP-lowering effect additive to propranolol in preclinical models,^25–27 while the Rho-kinase inhibitors Y-27632²⁸ and fasudil²⁹ showed comparable beneficial effects. Indeed, RhoA modulation using sodium ferulate³⁰ or diarylpropionitrile³¹ showed beneficial effects in preclinical PH, and interestingly, pointed out the relevance of the latter (which is an estrogen-receptor β agonist) in postmenopausal women. On the other hand, the receptor Mas also represents an alternative downstream target of the RAA pathway. Its activation showed promising effects in experimental models of cirrhosis, also reducing PP and liver fibrosis.³² Nevertheless, another study blocking the Mas receptor with A779 led to the same decrease in PP,³³ leaving the Mas receptor role in a paradigm.

Vasopressin, also named antidiuretic hormone, is a hormone that contributes to the regulation of water and electrolyte homeostasis and constricts arterioles, increasing vascular resistance and blood pressure. The blockage of vasopressin using conivaptan has been recently tested in an RCT and showed no beneficial effects on PP.³⁴ Indeed, previous data support the concept that vaptans may not only be ineffective but also have negative secondary effects in terms of morbidity and mortality in patients with cirrhosis.^35,36 Partial vasopressin agonists in the mesentery may have better projection. Indeed, a recent study demonstrated beneficial effects of FE 204038 reducing PP in cirrhotic rats,³⁷ and a recently started RCT evaluates the compound FE 204205 in cirrhotic patients with PH.³⁸

Promotion of vasodilation

Nitric oxide (NO) is a potent vasodilator synthesized by the NO synthase (NOS) that regulates vascular tone and inflammation; however, it becomes markedly deregulated in the cirrhotic liver. Several therapeutic approaches focused at increasing its levels, either by enhancing NO production (NOS-dependent strategies), or by providing NO as an exogenous source or decreasing NO degradation (NOS-independent strategies).

Delivering NO to precise cellular locations, like the liver sinusoid, represents a challenge. However, nanoparticle delivery has lately become an important and emerging field. In fact, recent studies using NO-releasing nanoparticles coated with vitamin A, which is mainly stored in HSCs in the liver, reduced PP in a preclinical cirrhotic model.³⁹ Similar effects were observed when NO synthesis was enhanced: the NOS cofactor tetrahydrobiopterin (sapropterin) and the NOS transcription enhancer (AVE 9488) decreased PP in cirrhotic animal models,^40,41 nevertheless no benefits were observed in an RCT evaluating the first.⁴² In this same strategy, a currently ongoing RCT will describe the effectiveness of serelaxin, a drug that has been used for the treatment of acute heart failure due its capability to activate the relaxin receptor and NOS.⁴³

The soluble guanylate cyclase (sGC) is the only known receptor for NO and represents its downstream mediator. When sGC is activated by NO, it induces the formation of the intermediate cyclic guanosine monophosphate (cGMP), which confers potent vasodilation. In this regard, the stimulation of the nonoxidized form of sGC or the oxidized and free-sGC form may represent novel approaches for activating cGMP production and subsequently ameliorate the vasoconstrictor environment. In fact, a recent study using the nonoxidized and free-sGC stimulator riociguat showed improved liver fibrosis and PP in cirrhotic animals.⁴⁴ However, no studies have evaluated the potential of activators of the oxidized form of sGC for the treatment of PH. Considering that oxidative stress plays a key role in cirrhosis and PH, and that sGC activators are able to generate cGMP even in these detrimental conditions,⁴⁵ their usefulness as a therapeutic option for PH deserves further investigation.

In addition to sGC strategies, there are other approaches aimed at potentiating the effects of cGMP by preventing its degradation by phosphodiesterase-5 (PDE-5). Indeed, different PDE-5 inhibitors showed lowering effects on PP in cirrhotic patients.^46–48

Transcriptional modulators

In addition to specific modulators of vasoactive molecules, other strategies rely on the modulation of transcription factors that regulate the expression of many of these proteins. For example, farnesoid X receptor (FXR) is a bile-acid-responsive transcription factor highly expressed in the liver that controls the expression of many genes involved in metabolic regulation, hepatic fibrosis, vascular homeostasis and inflammation, and thus it has been considered a promising therapeutic target in CLD. Obeticholic acid (OCA), a semisynthetic FXR agonist, has been tested in preclinical models of cirrhosis showing beneficial effects on PH by reducing the IHVR.⁴⁹ Indeed, different ongoing clinical trials are investigating its effects in advanced CLD,^50–52 including patients with NASH cirrhosis.^53,54 This drug, however, has raised some cases of overdose-related toxicity in patients with severe or even mild liver dysfunction, so its dosage needs to be carefully adjusted.⁵⁵ In addition to OCA, new nonsteroidal FXR agonists have been developed to evade enterohepatic recirculation. These drugs (e.g. PX201606, GS-9674), have been tested in animals with CLD showing increased endothelial NOS expression, reduced inflammatory response and improved liver injury.^56,57 The effects of these newly formulated compounds on advanced CLD and PH require further investigation.

On the other hand, statins are lipid-lowering drugs that have shown strong hepatosinusoidal protective effects in preclinical models of CLD, ultimately leading to PP decrease.^58–60 Underlying mechanisms of statins mostly rely on their capability to induce the expression of the transcription factor Kruppel-like factor 2 that leads to liver sinusoidal endothelial cell (LSEC) phenotype amelioration, HSC deactivation, and global improvement in hepatic injury.^61–66 Encouraged by the preclinical results, several clinical studies have tested statins in PH-cirrhotic patients. Recent analyses have shown that statins are associated with decreased risk of decompensation, death and hepatocellular carcinoma development.^67,68 Moreover, simvastatin has shown beneficial effects when administered alone⁶⁹ or combined with beta blockers.⁷⁰ Future and ongoing RCTs will extend our knowledge regarding the use of statins for the treatment of PH.⁷¹

Anticoagulants

It is widely accepted that cirrhotic patients have an imbalance in anti- and procoagulant factors, leading to both increased risk of bleedings and microthrombosis in the liver, which may in turn increase liver hypoxia and inflammation.⁷² Therefore, different anticoagulants have been lately tested in the setting of CLD with success in the prevention of hepatic fibrosis.⁷³ Indeed, the direct antithrombin enoxaparin has been shown to reduce PP and liver fibrosis in experimental CLD,⁷⁴ confirming at the bench side its clinical benefits on cirrhosis decompensation and survival.⁷⁵ A different anticoagulant strategy is the direct inhibitor of factor Xa rivaroxaban, which has been shown to reduce liver microthrombosis, HSC activation and PP in experimental models of cirrhosis.⁷⁶ Moreover, it is currently being tested in RCTs on patients with cirrhosis⁷⁷ or with portal-vein thrombosis.⁷⁸ Additional, ongoing RCTs will provide more data on the use of anticoagulants for CLD-patients.⁷⁹

Antiangiogenics

Angiogenesis is an important feature in the development of PH, being triggered by hypoxia and inflammation which are present during hepatic fibrogenesis.⁸⁰

Vascular endothelial growth factor (VEGF) is the main proangiogenic factor promoting neovascularization in the mesentery and contributes to the development of increased splanchnic vasodilation. Therefore, different studies have focused on blocking VEGF receptors (VEGFr) to decrease splanchnic circulation and improve PP. Initially, monoclonal antibodies and specific inhibitors of VEGFr2 were used in PH animals showing improvement in portosystemic collateral vessel formation but showing no effect on PP.^81,82 Subsequent preclinical studies investigated oral tyrosine kinase inhibitors that block VEGFr2, such as sorafenib,^83,84 brivanib^84,85 and regorafenib⁸⁶ and showed improved PP and systemic shunting in cirrhotic and noncirrhotic rats with PH. Indeed, tyrosine kinase inhibitors have also been shown to decrease liver fibrosis.⁸⁷ These beneficial preclinical results were confirmed in a small clinical trial where sorafenib significantly improved PH in patients with liver cirrhosis and hepatocellular carcinoma.⁸⁸

Apart from VEGF, other molecules such as pigment epithelium-derived factor (PEDF) or vasohibin-1 have been shown as potent endogenous inhibitors of angiogenesis. In fact, overexpression by adenovirus of PEDF or vashoihin-1 resulted in decreased mesenteric angiogenesis, portosystemic shunting, PH and liver fibrosis.^89,90 Nevertheless, no current RCTs are being performed following this approach. It is important to highlight that angiogenesis is not only deleterious but also required for repairmen of hepatic tissue during liver fibrosis resolution, therefore total angiogenesis blockade may not be a realistic therapeutic approach.

Cell death, oxidative stress and inflammation

Prevention of cell death

The main factor in the progression of cirrhosis is chronic liver injury. This is a scenario of persistent cell death (due to different etiologies), which leads to excessive inflammation and associated cytotoxicity, and oxidative stress. This sequence of events has led to the hypothesis that pharmacological inhibition of cell death may represent a therapeutic option for the treatment of PH and CLD (Figure 2).

Figure 2.

Schematic representation of different therapeutic approaches for portal hypertension based on their effect on apoptosis, oxidative stress or inflammation as main features of chronic liver damage.

Emricasan is an orally active pan-caspase inhibitor that has proven promising potential in the setting of CLD. Indeed, a preclinical study presented as a meeting abstract describes that CCl₄-cirrhotic rats receiving emricasan displayed improved PP and IHVR compared with vehicle-treated rats, in addition to improved liver function and microcirculation, and these effects were accompanied by improved LSEC and HSC phenotype and reduced inflammation.⁹¹ More recently, another study in bile-duct-ligated (BDL) mice reported similar effects of this caspase inhibitor.⁹² At the bedside, emricasan did not show positive effects in acute-on-chronic liver failure.⁹³ However, a proof-of-concept clinical study suggests that emricasan ameliorates PP in patients with compensated cirrhosis and severe PH.⁹⁴ The completion of a bigger ongoing clinical trial⁹⁵ may confirm these promising results in the near future.

These findings are in agreement with other studies assessing the use of caspase inhibitors in chronic liver diseases, such as NASH (reviewed elsewhere⁹⁶). Of note, inhibition of the apoptosis signal-regulating kinase 1 is another potential candidate strategy in CLD, as it has shown significant results in reducing the fibrosis stage of NASH patients.⁹⁷

Despite the exciting results, there is still controversy on the role of cell-death modulation in CLD. Indeed, a recent study suggests that the use of caspase inhibitors would not avoid cell death, as hepatocytes may still die from necrosis.⁹⁸ On the other hand, some vasoprotective drugs modulate hepatic fibrosis at least in part due to selective apoptosis of HSCs,⁶⁵ while other studies suggest that treatment with low doses of an apoptotic agent (gliotoxin) may achieve similar effects without affecting hepatocyte viability.⁹⁹

Future studies will clarify the usefulness of cell-death inhibition in a context where the injury is not present anymore, such as the regression of CLD after the removal of the hepatic injury.

Antioxidants

During liver damage, increased inflammation, mitochondrial damage and enzymatic alterations [i.e. xanthine and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases] induce oxidative stress. Antioxidants are molecules that compensate this oxidative stress by promoting the conversion of reactive oxygen species (ROS) into less reactive molecules, either by direct enzymatic activity or by transcriptional/post-transcriptional modulation of other enzymes. However, cirrhotic livers are known to produce reduced levels of antioxidants compared with control livers, thus further aggravating the increased oxidative stress in this setting.^100,101 For this reason, several studies aimed to develop pharmacological antioxidant-enhancing strategies for CLD. One of these is mitoquinone, a mitochondria-targeted antioxidant with oral administration approved for human use. This drug has already proved positive effects in preventing oxidative damage in models of liver diseases such as NASH or ischemia/reperfusion.^102,103 In a recent study, treatment with mitoquinone reduced PP and IHVR in two different preclinical models of CLD [CCl₄ and thioacetamide (TAA)] by reducing oxidative stress and fibrosis.¹⁰¹ Importantly, these antifibrotic effects were also validated in precision-cut liver slices from human tissue, suggesting potential applicability in clinical practice. Moreover, a recent abstract reports similar effects of this drug in the BDL rat model.¹⁰⁴

Apocynin is a natural antioxidant of vegetal origin which has a specific inhibitory effect on NADPH oxidase and thus has been studied for its antioxidant properties.^105–107 In this regard, a recent study assessed the effects of apocynin in a model of mild fibrosis.¹⁰⁸ Although authors described amelioration of markers of liver damage, oxidative stress, inflammation and fibrosis, these effects were not observed in a previous study using animals with advanced CLD probably due to a progressive reduction in NADPH oxidase activity during cirrhosis development.¹⁰⁹ This advocates for the use of NADPH oxidase inhibitors during progression but not at advanced stages of CLD. Indeed, a study using a new generation of NADPH oxidase inhibitor demonstrated anti-inflammatory and hepatoprotective effects in a preclinical model of NASH without significant fibrosis,¹¹⁰ altogether encouraging future studies to ascertain which would be the appropriate therapeutic window for this strategy in cirrhosis.

In addition to their protective effects against oxidative stress, antioxidants may also play an important role in ameliorating microvascular dysfunction, as they prevent the scavenging of NO by the superoxide anion (O₂⁻).¹⁰⁰ In this direction, back in 2006, Hernández-Guerra and collegues assessed whether acute administration of ascorbic acid would prevent the increase in HVPG associated with the defective ability of the cirrhotic endothelium to accommodate the postprandial increase in portal blood flow. Indeed, patients receiving vitamin C displayed lower HVPG after a meal compared with placebo, suggesting improved microvascular function.¹¹¹ Interestingly, a more recent publication demonstrated that consumption of dark chocolate had similar effects on the postprandial increase of HVPG.¹¹² Since then, several studies have addressed the role of antioxidant therapy in the improvement of NO bioavailability. In this regard, the modulation of the activity of the antioxidant enzyme superoxide dismutase (SOD) has proven promising effects in animal models of CLD.^113,114 In a study from 2011, administration of tempol, a SOD analog, improved the IHVR of cirrhotic rats in an NO-dependent manner.¹¹⁴ Similarly, a more recent study assessed the administration of a recombinant form of human manganese SOD in two different animal models of CLD resulting in improved liver hemodynamics, as well as reduced oxidative stress and liver fibrosis.¹¹⁵ Resveratrol is an antioxidant found in the skin of grapes that activates the histone deacetylase Sirt1, which regulates several vasoprotective pathways leading to NO overexpression.¹¹⁶ Recent studies have reported hepatic antifibrotic effects of resveratrol in models of mild liver injury linked to its antioxidant properties^117–119 while its administration to rats with severe PH reduced PP and hepatic fibrosis, and ameliorated hepatic microvascular dysfunction.¹²⁰

Strategies targeting inflammation

Anti-inflammatory strategies

Rapamycin is an immunosuppressor that negatively regulates the mammalian target of rapamycin (mTOR) complexes, which play a central role in the regulation of many of the cellular pathways including proliferation, inflammation, apoptosis and autophagy. In the field of CLD, rapamycin has shown the ability to reduce the PP in rats with PH due to its intrahepatic^121,122 and extrahepatic effects.^123,124

The Janus kinase 2 protein (JAK2) is involved in the toll-like receptor (TLR) signaling in response to lipopolysaccharide, and upregulates profibrotic and inflammatory genes. As commented above, AG490 is a specific inhibitor of JAK2 but it can also regulate the TLR signaling pathway. Recently, its potent antifibrotic and anti-inflammatory effects were proven in livers of BDL-cirrhotic rats, partially normalizing PH. Furthermore, the same study reported additional extrahepatic hemodynamic amelioration in the partial portal-vein ligation model,²⁶ while combination with NSBB achieved additive effects.²⁷

Epoxyeicosatrienoic acids (EETs) are products of the arachidonic acid metabolism with anti-inflammatory properties.¹²⁵ These molecules are further metabolized by the soluble epoxide hydrolase (sEH), thus inhibition of this enzyme represents a good strategy in maintaining or increasing EET levels. Indeed, the anti-inflammatory effects of the sEH inhibitor t-TUCB have been recently validated in steatotic livers.¹²⁶ In addition to these effects, EETs have also been described to show vasoactive properties,¹²⁷ thus suggesting additional potential in liver vascular diseases. Indeed, recent studies reported that t-TUCB treatment ameliorates PH in CCl₄-cirrhotic rats, altogether improving fibrogenesis and endothelial dysfunction^128,129 while additionally ameliorating extrahepatic circulation.¹³⁰ Although inflammatory markers were also downregulated by this inhibitor, whether the hemodynamic effects were additive or directly mediated by inflammation was not assessed. Despite these promising reports, there is some controversy regarding the role of EETs in cirrhosis, as another study reported opposite effects in the splanchnic territory.²¹

In addition to conventional anti-inflammatory pharmacological strategies, engineered nanoparticles represent an alternative therapeutic option with targetable delivery. Cerium oxide nanoparticles have been shown to behave as anti-inflammatory agents, with no exception in the liver. Indeed, these nanoparticles prevented macrophage infiltration and overexpression of hepatic inflammatory genes, causing a reduction in oxidative stress and improving PP in rats with mild PH.¹³¹

Antidiabetic drugs

As expected from drugs aimed at normalizing glucose levels, antidiabetic treatments usually target glucose and lipid transport, as well as metabolism. However, these drugs have also been reported to have vasoprotective effects associated with NO bioavailability, inflammation and oxidative stress.^132–134 In consequence, these beneficial effects have been assessed in CLD. One such pharmacological strategy is use of liraglutide. This glucagon-like peptide 1 (GLP-1) analog has shown the ability to ameliorate PH and liver microvascular function in cirrhotic animals by reducing HSC activation and the levels of inflammatory markers independently of the GLP-1 receptor.¹³⁵ In this same study, the effects of liraglutide were validated in different human models in vitro, thus shortening the gap between the preclinical study and clinical trials. Indeed, liraglutide has shown antifibrotic effects also in NASH patients,¹³⁶ thus representing a promising drug with high probabilities of success as a treatment for PH and CLD. Similarly, the antidiabetic drug metformin has shown improvement in liver hemodynamic and fibrosis, which were accompanied by a reduction in inflammation and oxidative stress.¹³⁷ Interestingly, the observed hemodynamic effects were complementary to the effects of NSBB. Lastly, fenofibrate, another antidiabetic drug with described positive vascular effects, also improved PP in cirrhotic rats in addition to hepatic fibrosis and microvascular function.¹³⁸

An additional strategy to these drugs is the use of antibodies that specifically block the interaction between metabolic hormones and their ligands. Leptin, the satiety hormone, is overexpressed in obese people, who may suffer from leptin resistance. Furthermore, this hormone has been implicated in fibrosis and is highly expressed in cirrhotic patients, probably due to inflammation.^139,140 Interestingly, the use of a competitive antibody against leptin receptor proved to be effective in ameliorating PP and IHVR in cirrhotic rats, suggesting that leptin is not only a marker in CLD but is also a targetable effector.¹⁴¹

Microbiota modulators

Intestinal bacteria are known to modulate splanchnic flow and thus participate in the PH-derived hyperdynamic syndrome. In addition, during cirrhosis, increased gut permeability allows translocation of bacteria or their products into the bloodstream, causing general and hepatic inflammation.^142,143 For this reason, different clinical trials have assessed the use of antibiotics (rifaximin,^144–146 norfloxacin¹⁴⁷) as prophylactic intervention against general infections in decompensated cirrhotic patients, which overall improved their outcome.

However, recent research suggests that the composition of the microbiota population may also play a role in gut permeability and, interestingly, in liver hemodynamics. In this regard, oral administration of the probiotic VSL#3 (a mix of four Lactobacillus species) prevented the increase in the systemic levels of inflammatory cytokines and vasodilators in a rat model of BDL cirrhosis¹⁴⁸ and ameliorated liver function and pro-inflammatory markers in cirrhotic patients compared with the placebo group.¹⁴⁹ Bifidobacterium pseudocatenulatum CECT7765 supplementation had similar anti-inflammatory features. On one hand, liver or blood macrophages isolated from cirrhotic animals and patients (respectively) switched to an anti-inflammatory M2 phenotype when treated in vitro with B. pseudocatenulatum¹⁵⁰ while on the other hand, oral administration of the bifidobacteria to BDL-cirrhotic rats improved their hepatic hemodynamic parameters, liver damage and markers of inflammation in vivo.¹⁵¹

These findings suggest that not only direct administration of bacteria but also diets that modify the gut microbiota could have therapeutic value in CLD and PH. Indeed, a recent clinical trial reported that cohorts of healthy controls and patients with cirrhosis have different microbiota populations, that microbiota diversity negatively correlates with the degree of cirrhosis, and that cirrhotic patients with diets that ensure higher microbiota diversity had lower risk of hospitalization.¹⁵² Dietary goods associated with microbiota diversity included fermented milk products, coffee, tea, dark chocolate and vegetables, while consumption of carbonated drinks (including caffeinated ones) was predictor of poor diversity. Interestingly, most of the microbiota-beneficial products are rich in polyphenols (antioxidants), thus holding a potential combined effect to that.

Strategies targeting fibrogenesis

As stated above, it is well known that chronic liver damage in combination with paracrine signaling from the activated endothelium lead to the activation of HSCs, promoting fibrogenesis.^63,153

Although most of the vasoprotective strategies described above ultimately lead to significant amelioration in fibrosis, there are a few pharmacological approaches that directly target the process of fiber formation/stabilization. One of these is simtuzumab, a monoclonal antibody against lysyl oxidase homologue 2 (LOXL2). LOXL2 is a protein that participates in the cross-linking of collagens and elastin. This protein is highly expressed in fibrotic livers (unlike control livers) and its inhibition with antibodies has shown positive results in preventing and reducing liver fibrosis in preclinical models.¹⁵⁴ Despite these promising results, simtuzumab proved to be ineffective in a recent phase II RCT in NASH-cirrhotic patients,¹⁵⁵ highlighting the controversy that is often found in the translation of some therapies from the laboratory to the clinic.

Cell therapy

The lack of pharmacologic therapeutic options to ameliorate PH and cirrhosis has prompted the use of regenerative therapies or cell-derived interventions. In 2006, Terai and colleagues performed the first clinical trial studying the autologous bone marrow cell infusion (ABMi) in decompensated cirrhotic patients, showing a decrease in Child-Pugh score as well as better liver function.¹⁵⁶ Latterly, infusion of mesenchymal stem cells (MSCs) from bone marrow or from umbilical cord to patients with liver cirrhosis demonstrated amelioration in hepatic fibrosis and function with increased serum albumin levels and with a good safety profile.¹⁵⁷ However, the last investigations in the field are focused on less invasive therapies using induced pluripotent stem cells (iPS).¹⁵⁸ iPS have been proposed as a new therapeutic option to replace damaged hepatocytes by healthy hepatocyte-like cells in CLD.¹⁵⁹ Nevertheless, hepatocyte-like cells induced by reprogramming methods remain immature without the specific hepatocyte characteristics such as detoxification or production of albumin and urea.¹⁶⁰ Along this theme, transplantation of human fetal hepatocytes¹⁶¹ was evaluated in patients with end-stage CLD; although the small population size of the study was an important limitation for obtaining a robust conclusion, model for end-stage liver disease (MELD) score and portosystemic encephalopathy episodes were ameliorated in transplanted patients. Even though several clinical trials evaluating stem cell therapies in CLD are still ongoing,^162–164 none of them specifically performs HVPG measurements; therefore, these RCTs will not provide new results about the effect of stem cells in PH.

On the other hand, preclinical studies have evaluated the effectiveness of cell-derived therapy ameliorating hepatic fibrosis, inflammation and liver hemodynamics using different sources and potency of stem cells in fibrotic and cirrhotic rodents. Specifically, human placenta-derived stem cells (PDSCs) are considered a promising therapeutic option for their proliferation and differentiation capacities, as well as their low immunogenicity potential.¹⁶⁵ In this sense, the anti-inflammatory and regenerative effects of chorionic plate-derived MSC transplantation in CCl₄-injured rats¹⁶⁶ and the amelioration in fibrosis and cirrhosis progression in fibrotic rodents receiving human amniotic membrane-derived mesenchymal¹⁶⁷ or epithelial stem cells¹⁶⁸ has been reported. In addition, transplantation of human amniotic MSCs in TAA-induced cirrhotic mice was able to restore the hepatic function and improve liver fibrosis;¹⁶⁹ importantly, this study suggested the PDSCs transplantation as a better therapeutic option in comparison with adipose tissue-derived MSCs.

Regarding the effects of stem cells on PH and hepatic microcirculation, much less is known. Brückner and colleagues suggested that transplantation of hepatocyte-like cells in vitro differentiated from rat adipose tissue MSCs into CCl₄-cirrhotic rats led to an amelioration in PH after 3 weeks of treatment without changes in liver dysfunction or fibrosis.¹⁷⁰ However, an ongoing preclinical study presented as a meeting abstract has shown the beneficial effects of transplantation of human amniotic stem cells (mesenchymal or epithelial) in CCl₄-induced cirrhotic rats with PH, improving HSC and LSEC phenotype, inflammation and liver function, resulting in an amelioration in PH and microvascular dysfunction.¹⁷¹

The promising results of cell therapy in preclinical models of CLD and PH support future and ongoing clinical trials using this strategy.

Lifestyle and dietary interventions

The basis of most of the abovementioned strategies is to improve deregulated processes in CLD (vasoconstriction, oxidative stress, etc.) with drugs or other molecules that specifically target these molecular pathways. Alternatively, wider effects on these pathological processes can also be achieved by modification in lifestyle; mainly diet and exercise.

Dietary approaches

The effects of certain diet components (dark chocolate, coffee/tea, fermented milk) on gut microbiota and its implications in CLD have been described above.^112,152,172 In summary, consumption of these products ensures a proper diversity in the gut microbiota while some of them also possess antioxidant properties, thus ameliorating liver damage and hemodynamics in CLD. In addition to these, the following dietary supplementations may have the potential to ameliorate PH.

Caffeine intake is extended worldwide, either in the form of coffee, tea or carbonated drinks. Independently of its effects on the gut microbiota,¹⁷³ caffeine consumption (in the form of coffee) has been associated with reduced liver fibrosis in precirrhotic patients.¹⁷⁴ Although there are no reports of its effects in PH in humans, prophylactic but also therapeutic treatment of BDL-cirrhotic rats with caffeine or caffeinated coffee ameliorated PP, liver inflammation and fibrosis, while also improving the extrahepatic vasculature.^175,176

Taurine is an amino-sulfonic acid ubiquitously expressed in mammals with many pleiotropic effects¹⁷⁷ and is also a component of the so-labeled ‘energy drinks’. It has been reported that taurine deficiency leads to CLD in preclinical models,¹⁷⁸ suggesting a protective role in cirrhosis. Indeed, oral taurine administration has been proven to ameliorate PP due to reduction in fibrosis and systemic vasodilation in a rat model of mild cirrhosis¹⁷⁹ while more recently, a clinical trial in a small cohort of patients with clinically significant PH (HVPG >12 mmHg) also reported reduction in PP.¹⁸⁰ Thus, consumption of low carbonated ‘energy drinks’ (which are rich in taurine, and also contain caffeine) may have a positive impact in PH.

Finally, curcumin is a dietary product most common in Asian countries but extended worldwide that possesses anti-inflammatory, antiangiogenic and antiproliferative properties.¹⁸¹ Indeed, its administration to BDL-cirrhotic rats decreased hepatic fibrosis and ameliorated liver endothelial phenotype while inducing splanchnic vasoconstriction, which led to a reduction in PP.¹⁸²

Lifestyle interventions

In addition to nutritional strategies, nonsedentary lifestyle exerts beneficial effects on CLD complications such as PH. ‘The SportDiet study’ demonstrated that moderate exercise in combination with a controlled diet reduced PP and body weight in overweight patients with compensated cirrhosis and PH.¹⁸³ Moreover, another RCT evaluating the effects of exercise and diet intervention in patients with cirrhosis and PH showed an improvement in HVPG determined before and postintervention.¹⁸⁴ Moreover, the impact of exercise therapy on cirrhosis and its complications has been extensively studied in patients^185,186 as well as in preclinical models.¹⁸⁷

Conclusion

The knowledge about the pathophysiology of CLD has improved dramatically in the last few years. Consequently, many preclinical studies reported novel treatments with promising improvements in PH and its complications that, importantly, act at different levels of the disease (either improving the microcirculation or the liver’s response to damage). Indeed, some of these proposed treatments are currently being tested in RCTs and could become new options for the treatment of CLD in the near future.

However, it seems obvious that the rate of success of the preclinical strategies at the bedside is still far from optimal. In this regard, new studies on the mechanisms of the disease (still to be fully understood) will provide new insights on novel targetable molecular pathways and metabolites. Nevertheless, we believe that in addition to the important research on drug development and efficacy, it is time to start wondering why these therapies fail in translation. What are the differences between preclinical models and current patients that make these therapies ineffective? Should the preclinical models integrate important variables present in humans, like comorbidities, epigenetics, aging, etc.? Are therapeutic windows different in humans? If so, could we ‘desensitize’ the human liver to these therapeutic windows? In our opinion, this second line of research could widen the current bottleneck in the translation of pharmacological strategies and reopen the box of failed therapeutic options in search of second chances.

Footnotes

Acknowledgements

MV and SG-M contributed equally to this article.

Funding

SG-M has a postdoctoral fellowship from the Stiftung für Leberkrankheiten and the Asociación Española Para el Estudio del Hígado. AF-I has a Sara Borrell contract from the Instituto de Salud Carlos III (CD15/00050). JG-S has received continued funding from the Instituto de Salud Carlos III (currently, FIS PI17/00012), the Spanish Ministry of Science, Innovation and Universities, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), the European Union Funds FEDER ‘una manera de hacer Europa’ and the Stiftung für Leberkrankheiten.

Conflict of interest statement

The authors declare that there is no conflict of interest.

ORCID iD

Jordi Gracia-Sancho

References

Bosch

Abraldes

Berzigotti

et al . The clinical use of HVPG measurements in chronic liver disease. Nat Rev Gastroenterol Hepatol 2009; 6: 573–582.

Ripoll

Groszmann

Garcia-Tsao

et al . Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 2007; 133: 481–488.

Sun

et al . Carvedilol for portal hypertension in cirrhosis: systematic review with meta-analysis. BMJ Open 2016; 6: e010902.

Kanwal

Tansel

Kramer

et al . Trends in 30-day and 1-year mortality among patients hospitalized with cirrhosis from 2004 to 2013. Am J Gastroenterol 2017; 112: 1287–1297.

Watanabe

Takashimizu

Nishizaki

et al . An endothelin A receptor antagonist induces dilatation of sinusoidal endothelial fenestrae: implications for endothelin-1 in hepatic microcirculation. J Gastroenterol 2007; 42: 775–782.

Feng

H-Q

Weymouth

Rockey

DC.

Endothelin antagonism in portal hypertensive mice: implications for endothelin receptor-specific signaling in liver disease. AJP Gastrointest Liver Physiol 2009; 297: G27–G33.

Zipprich

Schenkel

Gittinger

et al . Selective endothelin-A blockade decreases portal pressure in patients with cirrhosis: a pilot study combining a local intraarterial and systemic administration. J Hepatol 2016; 64: S247.

Tripathi

Therapondos

Ferguson

et al . Endothelin-1 contributes to maintenance of systemic but not portal haemodynamics in patients with early cirrhosis: a randomised controlled trial. Gut 2006; 55: 1290–1295.

Lebrec

Bosch

Jalan

et al . Hemodynamics and pharmacokinetics of tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis. Eur J Clin Pharmacol 2012; 68: 533–541.

10.

EU Clinical Trials Register, www.clinicaltrialsregister.eu/ctr-search/trial/2014-004624-21/DE#P. (accessed 17 July 2018)

11.

EU Clinical Trials Register, www.clinicaltrialsregister.eu/ctr-search/trial/2011-001139-22/AT. (accessed 17 July 2018)

12.

Heller

Schepke

Neef

et al . Increased urotensin II plasma levels in patients with cirrhosis and portal hypertension. J Hepatol 2002; 37: 767–772.

13.

Trebicka

Leifeld

Hennenberg

et al . Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats. Hepatology 2008; 47: 1264–1276.

14.

Gracia-Sancho

Maeso-Díaz

Fernández-Iglesias

et al . New cellular and molecular targets for the treatment of portal hypertension. Hepatol Int 2015; 9: 183–191.

15.

Gracia-Sancho

Laviña

Rodríguez-Vilarrupla

et al . Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers. J Hepatol 2007; 47: 220–227.

16.

Laleman

Van Landeghem

Van der Elst

et al . Nitroflurbiprofen, a nitric oxide-releasing cyclooxygenase inhibitor, improves cirrhotic portal hypertension in rats. Gastroenterology 2007; 132: 709–719.

17.

Gao

J-H

Wen

S-L

Yang

W-J

et al . Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. PLoS One 2013; 8: e69309.

18.

Gao

J-H

Wen

S-L

Feng

et al . Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats. Angiogenesis 2016; 19: 501–511.

19.

Rosado

Rodríguez-Vilarrupla

Gracia-Sancho

et al . Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats. Hepatology 2013; 58: 1424–1435.

20.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02802228. (accessed 17 July 2018)

21.

Di Pascoli

Zampieri

Verardo

et al . Inhibition of epoxyeicosatrienoic acid production in rats with cirrhosis has beneficial effects on portal hypertension by reducing splanchnic vasodilation. Hepatology 2016; 64: 923–930.

22.

Steib

Bilzer

Op den Winkel

et al . Treatment with the leukotriene inhibitor montelukast for 10 days attenuates portal hypertension in rat liver cirrhosis. Hepatology 2010; 51: 2086–2096.

23.

Bolognesi

Di Pascoli

Verardo

et al . Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis. World J Gastroenterol 2014; 20: 2555–2563.

24.

Tandon

Abraldes

Berzigotti

et al . Renin–angiotensin–aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis. J Hepatol 2010; 53: 273–282.

25.

Granzow

Schierwagen

Klein

et al . Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. Hepatology 2014; 60: 334–348.

26.

Wang

Yin

Dong

et al . Inhibition of Janus kinase-2 signalling pathway ameliorates portal hypertensive syndrome in partial portal hypertensive and liver cirrhosis rats. Dig Liver Dis 2015; 47: 315–323.

27.

Wang

Yin

et al . Combined administration of propranolol + AG490 offers better effects on portal hypertensive rats with cirrhosis. J Gastroenterol Hepatol 2016; 31: 1037–1044.

28.

Klein

Van Beuge

Granzow

et al . HSC-specific inhibition of Rho-kinase reduces portal pressure in cirrhotic rats without major systemic effects. J Hepatol 2012; 57: 1220–1227.

29.

Fukuda

Narahara

Kanazawa

et al . Effects of fasudil on the portal and systemic hemodynamics of patients with cirrhosis. J Gastroenterol Hepatol 2014; 29: 325–329.

30.

Wei

Yang

Wang

et al . Sodium ferulate lowers portal pressure in rats with secondary biliary cirrhosis through the RhoA/Rho-kinase signaling pathway: a preliminary study. Int J Mol Med 2014; 34: 1257–1267.

31.

Zhang

C-G

Zhang

Deng

W-S

et al . Role of estrogen receptor β selective agonist in ameliorating portal hypertension in rats with CCl4-induced liver cirrhosis. World J Gastroenterol 2016; 22: 4484–4500.

32.

Klein

Herath

Schierwagen

et al . Hemodynamic effects of the non-peptidic angiotensin-(1-7) agonist AVE0991 in liver cirrhosis. PLoS One 2015; 10: e0138732.

33.

Grace

Klein

Herath

et al . Activation of the MAS receptor by angiotensin-(1-7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis. Gastroenterology 2013; 145: 874–884.e5.

34.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT00592475. (accessed 17 July 2018)

35.

Wong

Bernardi

Horsmans

et al . Effects of satavaptan, an oral vasopressin V2 receptor agonist, on management of ascites and morbidity in liver cirrhosis in a long-term, placebo-controlled study. J Hepatol 2009; 50: S42–S43.

36.

European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010; 53: 397–417.

37.

Fernández-Varo

Oró

Cable

et al . Vasopressin 1a receptor partial agonism increases sodium excretion and reduces portal hypertension and ascites in cirrhotic rats. Hepatology 2016; 63: 207–216.

38.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02929407. (accessed 17 July 2018)

39.

Duong

HTT

Dong

et al . The use of nanoparticles to deliver nitric oxide to hepatic stellate cells for treating liver fibrosis and portal hypertension. Small 2015; 11: 2291–2304.

40.

Matei

Rodríguez-Vilarrupla

Deulofeu

et al . The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis. Hepatology 2006; 44: 44–52.

41.

Biecker

Trebicka

Kang

et al . Treatment of bile duct-ligated rats with the nitric oxide synthase transcription enhancer AVE 9488 ameliorates portal hypertension. Liver Int 2008; 28: 331–338.

42.

Reverter

Mesonero

Seijo

et al . Effects of sapropterin on portal and systemic hemodynamics in patients with cirrhosis and portal hypertension: a bicentric double-blind placebo-controlled study. Am J Gastroenterol 2015; 110: 985–992.

43.

EU Clinical Trials Register, www.clinicaltrialsregister.eu/ctr-search/trial/2015-004031-12/GB. (accessed 17 July 2018)

44.

Schwabl

Brusilovskaya

Supper

et al . The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats. Sci Rep 2018; 8: 9372.

45.

Buys

Zimmer

Chickering

et al . Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential. Nitric Oxide 2018; 78: 72–80.

46.

Lee

K-C

Yang

Y-Y

Wang

Y-W

et al . Acute administration of sildenafil enhances hepatic cyclic guanosine monophosphate production and reduces hepatic sinusoid resistance in cirrhotic patients. Hepatol Res 2008; 38: 1186–1193.

47.

Deibert

Schumacher

Y-O

Ruecker

et al . Effect of vardenafil, an inhibitor of phosphodiesterase-5, on portal haemodynamics in normal and cirrhotic liver – results of a pilot study. Aliment Pharmacol Ther 2006; 23: 121–128.

48.

Deibert

Lazaro

Stankovic

et al . Beneficial long term effect of a phosphodiesterase-5-inhibitor in cirrhotic portal hypertension: a case report with 8 years follow-up. World J Gastroenterol 2018; 24: 438–444.

49.

Verbeke

Farre

Trebicka

et al . Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014; 59: 2286–2298.

50.

EU Clinical Trials Register, www.clinicaltrialsregister.eu/ctr-search/trial/2016-002965-67/NL. (accessed 17 July 2018)

51.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01473524. (accessed 17 July 2018)

52.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02308111. (accessed 17 July 2018)

53.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02548351. (accessed 17 July 2018)

54.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03439254. (accessed 17 July 2018)

55.

US Food and Drug Administration. FDA Drug Safety Communication: FDA warns about serious liver injury with Ocaliva (obeticholic acid) for rare chronic liver disease, (publish date 9 September 2017). https://www.fda.gov/Drugs/DrugSafety/ucm576656.htm (accessed 17 July 2018)

56.

Baghdasaryan

Claudel

Gumhold

et al . Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO₃⁻ output. Hepatology 2011; 54: 1303–1312.

57.

Zhang

Wang

Liu

et al . Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 2009; 51: 380–388.

58.

Trebicka

Hennenberg

Laleman

et al . Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology 2007; 46: 242–253.

59.

Abraldes

Rodríguez-Vilarrupla

Graupera

et al . Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats. J Hepatol 2007; 46: 1040–1046.

60.

Meireles

Pasarin

Lozano

et al . Simvastatin attenuates liver injury in rodents with biliary cirrhosis submitted to hemorrhage/resuscitation. Shock 2017; 47: 370–377.

61.

Trebicka

Hennenberg

Odenthal

et al . Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J Hepatol 2010; 53: 702–712.

62.

Klein

Klö sel

Schierwagen

et al . Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats. Lab. Invest 2012; 92: 1440–1450.

63.

Marrone

Russo

Rosado

et al . The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins. J Hepatol 2013;58:98–103.

64.

Miao

Zeng

et al . Simvastatin suppresses the proangiogenic microenvironment of human hepatic stellate cells via the Kruppel-like factor 2 pathway. Rev Esp Enferm Dig 2015; 107: 63–71.

65.

Marrone

Maeso-Díaz

García-Cardena

et al . KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut 2015; 64: 1434–1443.

66.

Rodríguez

Raurell

Torres-Arauz

et al . A nitric oxide-donating statin decreases portal pressure with a better toxicity profile than conventional statins in cirrhotic rats. Sci Rep 2017; 7: 40461.

67.

Mohanty

Tate

Garcia-Tsao

Statins are associated with a decreased risk of decompensation and death in veterans with hepatitis c–related compensated cirrhosis. Gastroenterology 2016; 150: 430–440.e1.

68.

Simon

Bonilla

Yan

et al . Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: results from ERCHIVES. Hepatology 2016; 64: 47–57.

69.

Pollo-Flores

Soldan

Santos

et al . Three months of simvastatin therapy vs. placebo for severe portal hypertension in cirrhosis: a randomized controlled trial. Dig Liver Dis 2015; 47: 957–963.

70.

Abraldes

Villanueva

Aracil

et al . Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis. Gastroenterology 2016; 150: 1160–1170.e3.

71.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02465645. (accessed 17 July 2018)

72.

Tacke

Luedde

Trautwein

Inflammatory pathways in liver homeostasis and liver injury. Clin Rev Allergy Immunol 2009; 36: 4–12.

73.

Jairath

Burroughs

AK.

Anticoagulation in patients with liver cirrhosis: complication or therapeutic opportunity?

Gut 2013; 62: 479–482.

74.

Cerini

Vilaseca

Lafoz

et al . Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol 2016; 64: 834–842.

75.

Villa

Cammà

Marietta

et al . Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012; 143: 1253–1260.e4.

76.

Vilaseca

García-Calderó

Lafoz

et al . The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells. Hepatology 2017; 65: 2031–2044.

77.

EU Clinical Trials Register, www.clinicaltrialsregister.eu/ctr-search/trial/2014-005523-27/ES. (accessed 17 July 2018)

78.

EU Clinical Trials Register, www.clinicaltrialsregister.eu/ctr-search/trial/2016-003240-37/ES. (accessed 17 July 2018)

79.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02247414. (accessed 17 July 2018)

80.

Corpechot

Barbu

Wendum

et al . Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 2002; 35: 1010–1021.

81.

Fernandez

Vizzutti

Garcia-Pagan

et al . Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology 2004; 126: 886–894.

82.

Fernandez

Mejias

Angermayr

et al . Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats. J Hepatol 2005; 43: 98–103.

83.

Reiberger

Angermayr

Schwabl

et al . Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats. J Hepatol 2009; 51: 865–873.

84.

Yang

Y-Y

Liu

R-S

Lee

P-C

et al . Anti-VEGFR agents ameliorate hepatic venous dysregulation/microcirculatory dysfunction, splanchnic venous pooling and ascites of NASH-cirrhotic rat. Liver Int 2014; 34: 521–534.

85.

Lin

H-C

Huang

Y-T

Yang

Y-Y

et al . Beneficial effects of dual vascular endothelial growth factor receptor/fibroblast growth factor receptor inhibitor brivanib alaninate in cirrhotic portal hypertensive rats. J Gastroenterol Hepatol 2014; 29: 1073–1082.

86.

Uschner

Nikolova

Klein

et al . The multikinase inhibitor regorafenib improves portal hypertension in presence and absence of cirrhosis in rats. J Hepatol 2016; 64: S134–S135.

87.

Huang

Lin

et al . New insight into the anti-liver fibrosis effect of multitargeted tyrosine kinase inhibitors: from molecular target to clinical trials. Front Pharmacol 2015; 6: 300.

88.

Pinter

Sieghart

Reiberger

et al . The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma–a pilot study. Aliment Pharmacol Ther 2012; 35: 83–91.

89.

Mejias

Coch

Berzigotti

et al . Antiangiogenic and antifibrogenic activity of pigment epithelium-derived factor (PEDF) in bile duct-ligated portal hypertensive rats. Gut 2015; 64: 657–666.

90.

Coch

Mejias

Berzigotti

et al . Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats. Hepatology 2014; 60: 633–647.

91.

Gracia-Sancho

Contreras

Vila

et al . The pan caspase inhibitor emricasan improves the hepatic microcirculatory dysfunction of CCl₄-cirrhotic rats leading to portal hypertension amelioration and cirrhosis regression. Hepatology 2016; 64: 811–1050.

92.

Eguchi

Koyama

Wree

et al . Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension in a murine model of common bile-duct ligation. J Mol Med 2018; 96: 575–583.

93.

Mehta

Rousell

Burgess

et al . A placebo-controlled, multicenter, double-blind, phase 2 randomized trial of the pan-caspase inhibitor emricasan in patients with acutely decompensated cirrhosis. J Clin Exp Hepatol 2018; 8: 224–234.

94.

Garcia-Tsao

Fuchs

Shiffman

et al . Emricasan (IDN-6556) lowers portal pressure in patients with compensated cirrhosis and severe portal hypertension. Hepatology. Epub ahead of print 31 July 2018. DOI: 10.1002/hep.30199.

95.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02960204. (accessed 17 July 2018)

96.

Wilson

Kumar

Caspases in metabolic disease and their therapeutic potential. Cell Death Differ 2018; 25: 1010–1024.

97.

Loomba

Lawitz

Mantry

et al . The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology 2018; 67: 549–559.

98.

H-M

McGill

Chao

et al . Caspase inhibition prevents tumor necrosis factor-α-induced apoptosis and promotes necrotic cell death in mouse hepatocytes in vivo and in vitro. Am J Pathol 2016; 186: 2623–2636.

99.

Wright

Issa

Smart

et al . Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology 2001; 121: 685–698.

100.

Gracia-Sancho

Laviña

Rodríguez-Vilarrupla

et al . Increased oxidative stress in cirrhotic rat livers: A potential mechanism contributing to reduced nitric oxide bioavailability. Hepatology 2007; 47: 1248–1256.

101.

Vilaseca

García-Calderó

Lafoz

et al . Mitochondria-targeted antioxidant mitoquinone deactivates human and rat hepatic stellate cells and reduces portal hypertension in cirrhotic rats. Liver Int 2017; 37: 1002–1012.

102.

Chacko

Srivastava

Johnson

et al . Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis. Hepatology 2011; 54: 153–163.

103.

Mukhopadhyay

Horváth

Zsengellėr

et al . Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia-reperfusion: therapeutic potential of mitochondrially targeted antioxidants. Free Radic Biol Med 2012; 53: 1123–1138.

104.

Turkseven

Bolognesi

Brocca

et al . In cirrhotic rats, mitochondria-targeted antioxidant mitoquinone attenuates liver inflammation and fibrosis by modulating oxidative stress and mitophagy. J Hepatol 2018; 68: S365–S604.

105.

Petrônio

Zeraik

Fonseca

et al . Apocynin: chemical and biophysical properties of a NADPH oxidase inhibitor. Molecules 2013; 18: 2821–2839.

106.

Castro

Francini

Schinella

et al . Apocynin administration prevents the changes induced by a fructose-rich diet on rat liver metabolism and the antioxidant system. Clin Sci (Lond) 2012; 123: 681–692.

107.

Fan

Shan

Qian

et al . Protective effect of apocynin in an established alcoholic steatohepatitis rat model. Immunopharmacol Immunotoxicol 2012; 34: 633–638.

108.

Rahman

Muse

Khan

DMIO

et al . Apocynin prevented inflammation and oxidative stress in carbon tetra chloride induced hepatic dysfunction in rats. Biomed Pharmacother 2017; 92: 421–428.

109.

Gracia-Sancho

Laviña

Rodríguez-Vilarrupla

et al . Evidence against a role for NADPH oxidase modulating hepatic vascular tone in cirrhosis. Gastroenterology 2007; 133: 959–966.

110.

Bettaieb

Jiang

Sasaki

et al . Hepatocyte nicotinamide adenine dinucleotide phosphate reduced oxidase 4 regulates stress signaling, fibrosis, and insulin sensitivity during development of steatohepatitis in mice. Gastroenterology 2015; 149: 468–480.e10.

111.

Hernández-Guerra

García-Pagán

Turnes

et al . Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology 2006; 43: 485–491.

112.

De Gottardi

Berzigotti

Seijo

et al . Postprandial effects of dark chocolate on portal hypertension in patients with cirrhosis: results of a phase 2, double-blind, randomized controlled trial. Am J Clin Nutr 2012; 96: 584–590.

113.

Lavina

Gracia-Sancho

Rodriguez-Vilarrupla

et al . Superoxide dismutase gene transfer reduces portal pressure in CCl4 cirrhotic rats with portal hypertension. Gut 2009; 58: 118–125.

114.

García-Calderó

Rodríguez-Vilarrupla

Gracia-Sancho

et al . Tempol administration, a superoxide dismutase mimetic, reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol 2011; 54: 660–665.

115.

Guillaume

Rodriguez-Vilarrupla

Gracia-Sancho

et al . Recombinant human manganese superoxide dismutase reduces liver fibrosis and portal pressure in CCl4-cirrhotic rats. J Hepatol 2013; 58: 240–246.

116.

Gracia-Sancho

Villarreal

Zhang

et al . Activation of SIRT1 by resveratrol induces KLF2 expression conferring an endothelial vasoprotective phenotype. Cardiovasc Res 2010; 85: 514–519.

117.

Chan

C-C

Lee

K-C

Huang

Y-H

et al . Regulation by resveratrol of the cellular factors mediating liver damage and regeneration after acute toxic liver injury. J Gastroenterol Hepatol 2014; 29: 603–613.

118.

Kessoku

Imajo

Honda

et al . Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis. Sci Rep 2016; 6: 22251.

119.

Szkudelski

Szkudelska

Potential of resveratrol in mitigating metabolic disturbances induced by ethanol. Biomed Pharmacother 2018; 101: 579–584.

120.

Di Pascoli

Diví

Rodríguez-Vilarrupla

et al . Resveratrol improves intrahepatic endothelial dysfunction and reduces hepatic fibrosis and portal pressure in cirrhotic rats. J Hepatol 2013; 58: 904–910.

121.

Wang

Yan

Wang

et al . Rapamycin ameliorates inflammation and fibrosis in the early phase of cirrhotic portal hypertension in rats through inhibition of mTORC1 but not mTORC2. PLoS One 2014; 9: e83908.

122.

Biecker

De Gottardi

Neef

et al . Long-term treatment of bile duct-ligated rats with rapamycin (sirolimus) significantly attenuates liver fibrosis: analysis of the underlying mechanisms. J Pharmacol Exp Ther 2005; 313: 952–961.

123.

Mejias

Garcia-Pras

Gallego

et al . Relevance of the mTOR signaling pathway in the pathophysiology of splenomegaly in rats with chronic portal hypertension. J Hepatol 2010; 52: 529–539.

124.

K-C

Huang

H-C

Chang

et al . Effect of sirolimus on liver cirrhosis and hepatic encephalopathy of common bile duct-ligated rats. Eur J Pharmacol 2018; 824: 133–139.

125.

Spector

Fang

Snyder

et al . Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function. Prog Lipid Res 2004; 43: 55–90.

126.

López-Vicario

Alcaraz-Quiles

García-Alonso

et al . Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: role for omega-3 epoxides. Proc Natl Acad Sci. U S A 2015; 112: 536–541.

127.

Khan

Falck

Manthati

et al . Epoxyeicosatrienoic acid analog attenuates angiotensin II hypertension and kidney injury. Front Pharmacol 2014; 5: 216.

128.

Deng

Zhu

Lin

et al . Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis. Prostaglandins Other Lipid Mediat 2017; 131: 67–74.

129.

Zhang

C-H

Zheng

Gui

et al . Soluble epoxide hydrolase inhibition with t-TUCB alleviates liver fibrosis and portal pressure in carbon tetrachloride-induced cirrhosis in rats. Clin Res Hepatol Gastroenterol 2018; 42: 118–125.

130.

Huang

Qin

Sun

et al . Inhibition of soluble epoxide hydrolase reduces portal pressure by protecting mesenteric artery myogenic responses in cirrhotic rats. Prostaglandins Other Lipid Mediat 2017; 131: 17–24.

131.

Oró

Yudina

Fernández-Varo

et al . Cerium oxide nanoparticles reduce steatosis, portal hypertension and display anti-inflammatory properties in rats with liver fibrosis. J Hepatol 2016; 64: 691–698.

132.

Shiraki

Oyama

Komoda

et al . The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis 2012; 221: 375–382.

133.

Saisho

Metformin and inflammation: its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets 2015; 15: 196–205.

134.

Stolarz

Farris

Wiley

et al . Fenofibrate attenuates neutrophilic inflammation in airway epithelia: potential drug repurposing for cystic fibrosis. Clin Transl Sci 2015; 8: 696–701.

135.

De Mesquita

Guixé-Muntet

Fernández-Iglesias

et al . Liraglutide improves liver microvascular dysfunction in cirrhosis: evidence from translational studies. Sci Rep 2017; 7: 3255.

136.

Armstrong

Gaunt

Aithal

et al . Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016; 387: 679–690.

137.

Tripathi

Erice

Lafoz

et al . Metformin reduces hepatic resistance and portal pressure in cirrhotic rats. Am J Physiol Gastrointest Liver Physiol 2015; 309: G301–G309.

138.

Rodríguez-Vilarrupla

Laviña

García-Calderó

et al . PPARα activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats. J Hepatol 2012; 56: 1033–1039.

139.

Zhang

Niu

Yan

et al . Stat3 pathway correlates with the roles of leptin in mouse liver fibrosis and sterol regulatory element binding protein-1c expression of rat hepatic stellate cells. Int J Biochem Cell Biol 2013; 45: 736–744.

140.

Zhai

Yan

Fan

et al . The β-catenin pathway contributes to the effects of leptin on SREBP-1c expression in rat hepatic stellate cells and liver fibrosis. Br J Pharmacol 2013; 169: 197–212.

141.

Delgado

Gracia-Sancho

Marrone

et al . Leptin receptor blockade reduces intrahepatic vascular resistance and portal pressure in an experimental model of rat liver cirrhosis. Am J Physiol Gastrointest Liver Physiol 2013; 305: G496–G502.

142.

Zhao

T-Y

L-P

C-Y

et al . IGF-1 decreases portal vein endotoxin via regulating intestinal tight junctions and plays a role in attenuating portal hypertension of cirrhotic rats. BMC Gastroenterol 2015; 15: 77.

143.

Gómez-Hurtado

Such

Francés

Microbioma y traslocación bacteriana en la cirrosis. Gastroenterol Hepatol 2016; 39: 687–696.

144.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02508623. (accessed 17 July 2018)

145.

EU Clinical Trials Register, www.clinicaltrialsregister.eu/ctr-search/trial/2012-002890-71/DK. (accessed 17 July 2018)

146.

EU Clinical Trials Register, www.clinicaltrialsregister.eu/ctr-search/trial/2013-004708-20/GB. (accessed 17 July 2018)

147.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01134692. (accessed 17 July 2018)

148.

Rincón

Vaquero

Hernando

et al . Oral probiotic VSL#3 attenuates the circulatory disturbances of patients with cirrhosis and ascites. Liver Int 2014; 34: 1504–1512.

149.

Dhiman

Rana

Agrawal

et al . Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology 2014; 147: 1327–1337.e3.

150.

Moratalla

Caparrós

Juanola

et al . Bifidobacterium pseudocatenulatum CECT7765 induces an M2 anti-inflammatory transition in macrophages from patients with cirrhosis. J Hepatol 2016; 64: 135–45.

151.

Gómez-Hurtado

Zapater

Portune

et al . Improved hemodynamic and liver function in portal hypertensive cirrhotic rats after administration of B. pseudocatenulatum CECT 7765. Eur J Nutr. Epub ahead of print 10 May 2018. DOI: 10.1007/s00394-018-1709-y.

152.

Bajaj

Idilman

Mabudian

et al . Diet affects gut microbiota and modulates hospitalization risk differentially in an international cirrhosis cohort. Hepatology 2018; 68: 234–247.

153.

Marrone

Shah

Gracia-Sancho

Sinusoidal communication in liver fibrosis and regeneration. J Hepatol 2016; 65: 608–617.

154.

Ikenaga

Peng

Z-W

Vaid

et al . Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. Gut 2017; 66: 1697–1708.

155.

Harrison

Abdelmalek

Caldwell

et al . Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology 2018; 155: 1140–1153.

156.

Terai

Ishikawa

Omori

et al . Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells 2006; 24: 2292–2298.

157.

Lyra

Soares

MBP

da Silva

LFM

et al . Infusion of autologous bone marrow mononuclear cells through hepatic artery results in a short-term improvement of liver function in patients with chronic liver disease: a pilot randomized controlled study. Eur J Gastroenterol Hepatol 2010; 22: 33–42.

158.

Hannoun

Steichen

Dianat

et al . The potential of induced pluripotent stem cell derived hepatocytes. J Hepatol 2016; 65: 182–199.

159.

Nagamoto

Takayama

Ohashi

et al . Transplantation of a human iPSC-derived hepatocyte sheet increases survival in mice with acute liver failure. J Hepatol 2016; 64: 1068–1075.

160.

Liu

Ikeda

et al . Hepatocyte-like cells differentiated from human induced pluripotent stem cells: relevance to cellular therapies. Stem Cell Res 2012; 9: 196–207.

161.

Pietrosi

Vizzini

Gerlach

et al . Phases I–II matched case-control study of human fetal liver cell transplantation for treatment of chronic liver disease. Cell Transplant 2015; 24: 1627–1638.

162.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01560845. (accessed 17 July 2018)

163.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03209986. (accessed 17 July 2018)

164.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01573923. (accessed 17 July 2018)

165.

Parolini

Alviano

Bagnara

et al . Concise review: isolation and characterization of cells from human term placenta: outcome of the first international workshop on placenta derived stem cells. Stem Cells 2008; 26: 300–311.

166.

Jung

Choi

Lee

et al . Human placenta-derived mesenchymal stem cells promote hepatic regeneration in ccl4 -injured rat liver model via increased autophagic mechanism. Stem Cells 2013; 31: 1584–1596.

167.

Zhang

Jiang

Miao

Transplanted human amniotic membrane-derived mesenchymal stem cells ameliorate carbon tetrachloride-induced liver cirrhosis in mouse. PLoS One 2011; 6: e16789.

168.

Manuelpillai

Lourensz

Vaghjiani

et al . Human amniotic epithelial cell transplantation induces markers of alternative macrophage activation and reduces established hepatic fibrosis. PLoS One 2012; 7: e38631.

169.

Lee

P-H

C-T

Hsiao

C-C

et al . Antifibrotic activity of human placental amnion membrane-derived CD34+ mesenchymal stem/progenitor cell transplantation in mice with thioacetamide-induced liver injury. Stem Cells Transl Med 2016; 5: 1473–1484.

170.

Brückner

Zipprich

Hempel

et al . Improvement of portal venous pressure in cirrhotic rat livers by systemic treatment with adipose tissue-derived mesenchymal stromal cells. Cytotherapy 2017; 19: 1462–1473.

171.

Fernández-Iglesias

Pietrosi

Pampalone

et al . Stem cells as a new therapeutic strategy for portal hypertension and cirrhosis. J Hepatol 2018; 68: S8–S9.

172.

Gracia-Sancho

Bosch

Is it tea time for portal hypertension?

Clin Sci 2014; 126: 631–632.

173.

Cowan

Palmnäs

MSA

Yang

et al . Chronic coffee consumption in the diet-induced obese rat: impact on gut microbiota and serum metabolomics. J Nutr Biochem 2014; 25: 489–495.

174.

Modi

Feld

Park

et al . Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology 2010; 51: 201–209.

175.

Hsu

S-J

Lee

F-Y

Wang

S-S

et al . Caffeine ameliorates hemodynamic derangements and portosystemic collaterals in cirrhotic rats. Hepatology 2015; 61: 1672–1684.

176.

Arauz

Zarco

Hernández-Aquino

et al . Coffee consumption prevents fibrosis in a rat model that mimics secondary biliary cirrhosis in humans. Nutr Res 2017; 40: 65–74.

177.

Huxtable

RJ.

Physiological actions of taurine. Physiol Rev 1992; 72: 101–163.

178.

Warskulat

Borsch

Reinehr

et al . Chronic liver disease is triggered by taurine transporter knockout in the mouse. FASEB J 2006; 20: 574–576.

179.

Liang

Deng

Lin

Z-X

et al . Attenuation of portal hypertension by natural taurine in rats with liver cirrhosis. World J Gastroenterol 2009; 15: 4529–4537.

180.

Schwarzer

Kivaranovic

Mandorfer

et al . Randomised clinical study: the effects of oral taurine 6g/day vs placebo on portal hypertension. Aliment Pharmacol Ther 2018; 47: 86–94.

181.

Bachmeier

Killian

Melchart

The role of curcumin in prevention and management of metastatic disease. Int J Mol Sci 2018; 19: 1716.

182.

Hsu

S-J

Lee

J-Y

Lin

T-Y

et al . The beneficial effects of curcumin in cirrhotic rats with portal hypertension. Biosci Rep 2017; 37: BSR20171015.

183.

Berzigotti

Albillos

Villanueva

et al . Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: the SportDiet study. Hepatology 2017; 65: 1293–1305.

184.

Macías-Rodríguez

Ilarraza-Lomelí

Ruiz-Margáin

et al . Changes in hepatic venous pressure gradient induced by physical exercise in cirrhosis: results of a pilot randomized open clinical trial. Clin Transl Gastroenterol 2016; 7: e180.

185.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02776553. (accessed 17 July 2018)

186.

US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02949505. (accessed 17 July 2018)

187.

Lafoz

Vilaseca

García-Calderó

et al . Impacto del ejercicio con y sin dieta en la regresión de la cirrosis experimental en ratas tras la detención del agente etiológico hepatotóxico. Gastroenterol Hepatol 2018; 41: 24.

Advances in therapeutic options for portal hypertension

Abstract

Keywords

Introduction

Vasoprotective strategies

Vasomodulators

Inhibition of vasoconstriction

Promotion of vasodilation

Transcriptional modulators

Anticoagulants

Antiangiogenics

Cell death, oxidative stress and inflammation

Prevention of cell death

Antioxidants

Strategies targeting inflammation

Anti-inflammatory strategies

Antidiabetic drugs

Microbiota modulators

Strategies targeting fibrogenesis

Cell therapy

Lifestyle and dietary interventions

Dietary approaches

Lifestyle interventions

Conclusion

Footnotes

Acknowledgements

Funding

Conflict of interest statement

ORCID iD

References