Effect of liver resection-induced increases in hepatic venous pressure gradient on development of postoperative acute kidney injury

Background The impact of changes in portal pressure before and after liver resection (defined as ΔHVPG) on postoperative kidney function remains unknown. Therefore, we investigated the effect of ΔHVPG on (i) the incidence of postoperative AKI and (ii) the renin-angiotensin system (RAAS) and sympathetic nervous system (SNS) activity. Methods We included 30 patients undergoing partial liver resection. Our primary outcome was postoperative AKI according to KDIGO criteria. For our secondary outcome we assessed the plasma renin, aldosterone, noradrenaline, adrenaline, dopamine and vasopressin concentrations prior and 2 h after induction of anaesthesia, on the first and fifth postoperative day. HVPG was measured prior and immediately after liver resection. Results ΔHVPG could be measured in 21 patients with 12 patients HVPG showing increases in HVPG (∆HVPG≥1 mmHg) while 9 patients remained stable. AKI developed in 7/12 of patients with increasing HVPG, but only in 2/9 of patients with stable ΔHVPG (p = 0.302). Noradrenalin levels were significantly higher in patients with increasing ΔHVPG than in patients with stable ΔHVPG. (p = 0.009). Biomarkers reflecting RAAS and SNS activity remained similar in patients with increasing vs. stable ΔHVPG. Conclusions Patients with increased HVPG had higher postoperative creatinine concentrations, however, the incidence of AKI was similar between patients with increased versus stable HVPG.

Microbiota transplants from feces or gut content attenuated portal hypertension and portosystemic collaterals in cirrhotic rats

Liver cirrhosis and portal hypertension is the end of chronic liver injury with hepatic, splanchnic and portosystemic collateral systems dysregulation. Liver injury is accompanied by gut dysbiosis whereas dysbiosis induces liver fibrosis, splanchnic angiogenesis and dysregulated vascular tones vice versa, making portal hypertension aggravated. It has been proved that intestinal microbiota transplantation alleviates dysbiosis. Nevertheless, the influences of microbiota transplantation on cirrhosis related portal hypertension are not so clear. Liver cirrhosis with portal hypertension was induced by bile duct ligation in rats. Sham rats were surgical controls. Rats randomly received vehicle, fecal or gut (terminal ileum) material transplantation. The results showed that microbiota transplantation from feces or gut material significantly reduced portal pressure in cirrhotic rats (P = .010, .044). Hepatic resistance, vascular contractility, fibrosis and relevant protein expressions were not significantly different among cirrhotic rats. However, microbiota transplantation ameliorated splanchnic hyperdynamic flow and vasodilatation. Mesenteric angiogenesis, defined by whole mesenteric window vascular density, decreased in both transplantation groups and phosphorylated eNOS was downregulated. Portosystemic shunts determined by splenorenal shunt flow decreased in both transplantation groups (P = .037, .032). Shunting severity assessed by microsphere distribution method showed consistent results. Compared to sham rats, cirrhotic rats lacked Lachnospiraceae. Both microbiota transplants increased Bifidobacterium. In conclusion, microbiota transplantation in cirrhotic rats reduced portal pressure, alleviated splanchnic hyperdynamic circulation and portosystemic shunts. The main beneficial effects may be focused on portosystemic collaterals-related events, such as hepatic encephalopathy and gastroesophageal variceal hemorrhage. Further clinical investigations are mandatory.

Multistage closure of a congenital extrahepatic portosystemic shunt

Background Congenital extrahepatic portosystemic shunts (CEPS) are rare shunts connecting the extrahepatic portal system with the inferior vena cava. Shunt dimensions and the risk of portal hypertension determines the closure strategy. Endovascular treatment is indicated for single stage occlusion of longer length shunts, whereas the remaining shunt types are preferentially surgically occluded. Herein we describe the technical details of a novel endovascular treatment for short length CEPS. Case presentation A 15-years-old male with a short length CEPS complicated with multinodular liver disease was submitted to a multistage closure, as indicated by the high portal pressure values during shunt balloon occlusion venography. Initially a transjugular intrahepatic portosystemic shunt (TIPS) was created and the CEPS occluded with an atrial septal defect occluder. In a second procedure the TIPS was embolized with a flow reductor stent and an amplatzer vascular plug II. At a 1 year follow up the liver nodules size reduced, the patient remains asymptomatic, and the shunt adequately closed. Conclusion This paper outlines the potential use of a TIPS and an atrial septal defect occluder combination in complex CEPS, supporting its usage as an alternative to the standard surgical treatment. Level of Evidence: Level 4, Case report.

Impact of propofol sedation on the diagnostic accuracy of hepatic venous pressure gradient measurements in patients with cirrhosis

Background Measurement of the hepatic venous pressure gradient (HVPG) is the gold standard to evaluate the presence and severity of portal hypertension. The procedure is generally safe and well tolerated, but nevertheless, some patients demand for sedation. However, it is unknown whether propofol sedation would impair the accuracy of portal pressure measurements. Methods This is a prospective observational cohort study including cirrhotic patients with suspected portal hypertension undergoing invasive measurement of HVPG. Measurements of HVPG were performed in awake condition as well as under sedation with propofol infusion. Results In total, 37 patients were included. Mean HVPG in awake condition was 15.9 mmHg (IQR 13–19) and during sedation 14.1 mmHg (IQR 12–17). While measures of free hepatic vein pressure (FHVP) were not altered after propofol sedation (p = 0.34), wedged hepatic vein pressure values (WHVP) decreased in an average by 2.05 mmHg (95% CI − 2.46 to − 1.16; p < 0.001) which was proportional to the magnitude of HVPG. In 31 out of 37 patients (83.8%), portal hypertension with HVPG ≥ 12 mmHg was found. Under sedation with propofol, two patients (5.4%) with borderline values would have been incorrectly classified as < 12 mmHg. After adjustment for the average difference of − 10%, all patients were correctly classified. Intraclass correlation coefficient between HVPG measurement in awake condition and under propofol sedation was 0.927 (95% CI 0.594–0.975). Conclusions Propofol sedation during HVPG measurements is generally safe, however it may lead to relevant alterations of HVPG readings.

Impact of lifestyle interventions targeting physical exercise and caloric intake on cirrhosis regression in rats

In patients, advanced cirrhosis only regresses partially once the etiological agent is withdrawn. Animal models for advanced cirrhosis regression are missing. Lifestyle interventions (LI) have shown to improve steatosis, inflammation, fibrosis and portal pressure in liver disease. We aimed at characterizing cirrhosis regression after etiological agent removal in experimental models of advanced cirrhosis and to study the impact of different LI on it. Advanced cirrhosis was induced in rats either by CCl4 or by thioacetamide (TAA) administration. Systemic and hepatic hemodynamics, liver fibrosis, hepatic stellate cell (HSC) activation, hepatic macrophage infiltration and metabolic profile were evaluated after 48h, 4 weeks or 8 weeks of etiological agent removal. The impact of LI consisting in caloric restriction (CR) or moderate endurance exercise (MEE) during the 8-week regression process was analyzed. The effect of MEE was also evaluated in early cirrhotic and in healthy rats. A significant reduction in portal pressure (PP), liver fibrosis and HSC activation was observed during regression. However, these parameters remained above those in healthy animals. During regression, animals markedly worsened their metabolic profile. CR although preventing those metabolic disturbances did not further reduce PP, hepatic fibrosis or HSC activation. MEE also prevented metabolic disturbances, without enhancing, but even attenuating the reduction of PP, hepatic fibrosis and HSC activation achieved by regression. MEE also worsened hepatic fibrosis in early-TAA cirrhosis and in healthy rats.

Cyclic GMP in Liver Cirrhosis—Role in Pathophysiology of Portal Hypertension and Therapeutic Implications

The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the “NO-paradox”, referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies.

Electroacupuncture attenuates vascular hyporeactivity in a rat model of portal hypertension induced by bile duct ligation

Background: A hyperdynamic circulation and impaired vascular responsiveness to vasoconstrictors are observed in portal hypertension (PHT) rats. Inflammation is a major contributor to the hyperdynamic circulation state in murine models of PHT. Electroacupuncture (EA) may ameliorate the inflammatory response and limit arterial vasodilatation and portal pressure. This study investigated the possible mechanisms underlying putative hemodynamics effects of EA in normal and PHT rats. Methods: PHT was induced by bile duct ligation (BDL) surgery over 4 weeks in rats. Sham-operated and BDL rats were treated with low-frequency EA (2 Hz) at ST36 10 min three times weekly for one or two consecutive weeks (for a total of 3 or 7 treatments, respectively). Serum tumor necrosis factor-α (TNF-α), nitrite/nitrate (NOx) and 6-keto-prostaglandin F1α (6-keto-PGF1α) were analyzed, and hemodynamic variation and contractile responses to phorbol-12,13-dibutyrate and phenylephrine in aortic and superior mesenteric arterial rings were recorded. Inducible (i) and endothelial (3) nitric oxide synthase (NOS), cyclooxygenase-1 (COX-1), and protein kinase C-α (PKC-α) levels were determined by Western blotting. Results: EA significantly reduced portal pressure and serum TNF-α, NOx and 6-keto-PGF1α levels compared to the untreated BDL group, enhanced maximum contractile responses in the aorta, up-regulated PKC-α, and down-regulated iNOS and COX-1 levels. In addition, EA decreased the aortic angiogenesis signaling cascade, reflected by down-regulation of vascular endothelial growth factor (VEGF) abundance and transforming growth factor β receptor (TGFβR)I/II expression, as assessed by immunostaining. Conclusion: EA attenuates TNF-α, NO and 6-keto-PGF1α overproduction, modulates the vascular levels of constitutive NOS and PKC-α, blunts the development of the angiogenesis cascade, and enhances vascular contractile force in PHT rats.