Splanchnic vasodilatation contributes to the development and aggravation of portal hypertension (PHT). We previously demonstrated that in cirrhosis, angiotensin- mediates splanchnic vasodilatation through the Mas receptor (MasR). In this study, we investigated whether the recently characterized second receptor for angiotensin-(1-7), Mas-related G protein-coupled receptor type D (MrgD), contributes to splanchnic vasodilatation in cirrhotic and noncirrhotic PHT. Splanchnic vascular hemodynamic and portal pressure were determined in two rat models of cirrhotic PHT and a rat model with noncirrhotic PHT, treated with either MrgD blocker D-Pro7 -Ang-(1-7) (D-Pro) or MasR blocker A779. Gene and protein expression of MrgD and MasR were measured in splanchnic vessels and livers of cirrhotic and healthy rats and in patients with cirrhosis and healthy subjects. Mesenteric resistance vessels isolated from cirrhotic rats were used in myographs to study their vasodilatory properties. MrgD was up-regulated in cirrhotic splanchnic vessels but not in the liver. In cirrhotic rats, treatment with D-Pro but not A779 completely restored splanchnic vascular resistance to a healthy level, resulting in a 33% reduction in portal pressure. Mesenteric vessels pretreated with D-Pro but not with A779 failed to relax in response to acetylcholine. There was no splanchnic vascular MrgD or MasR up-regulation in noncirrhotic PHT; thus, receptor blockers had no effect on splanchnic hemodynamics. Conclusion: MrgD plays a major role in the development of cirrhotic PHT and is a promising target for the development of novel therapies to treat PHT in cirrhosis. Moreover, neither MrgD nor MasR contributes to noncirrhotic PHT.

Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients’ clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1–7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1–-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1–7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1–7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.

Evidence suggests that the renin angiotensin system (RAS) may play a role in the pathological splanchnic vasodilatation that leads to a hyperdynamic circulation in cirrhosis. An impaired contractile response to the angiotensin II peptide of the classical RAS system has been described in animal models of cirrhosis and in vivo in cirrhotic subjects. Furthermore, in experimental cirrhosis, the so-called alternate arm of the RAS was found to be upregulated and its effector peptide, angiotensin-(1-7) was shown to attenuate splanchnic vascular tone. The aim of this study was to explore the relevance of these findings to human disease. Omental arteries from cirrhotic and controls subjects were studied in isolation using a wire myograph. Varied protocols to evaluate the vasoactivity of RAS mediators were enacted. The contractile response to angiotensin II was comparable in cirrhotic vs control splanchnic arteries (61 +/- 9 vs 68 +/- 11% KPSS, respectively). Despite this, however, arterial contractility of the cirrhotic vessels correlated negatively with Child Pugh score (p = 0.0003, r = -0.83) and there was evidence that angiotensin II-induced contractility was increased in early cirrhosis. Angiotensin II-induced contractility was attenuated by angiotensin(1-7) in cirrhotic and control arteries, however, adrenergic responses were not affected by angiotensin-(1-7). Contractile responses to angiotensin II are preserved in narrow lumen human cirrhotic splanchnic arteries and are comparatively augmented in early disease. Angiotensin-(1-7) had no vasodilatory effect on adrenergic tone, however, attenuated angiotensin II-induced contractility, possibly through an Ang-(1-7)-AT1R interaction, and thus may contribute to pathological vasodilatation in human cirrhosis.

We describe the first case of a patient undergoing orthoptic liver transplantation for acquired generalized lipodystrophy-related nonalcoholic steatohepatitis who developed severe recurrence of nonalcoholic fatty liver disease in the first few months posttransplant but responded rapidly to the administration of exogenous leptin. The beneficial effects of therapy were supported by histology along with magnetic resonance spectroscopy studies, which demonstrated that leptin therapy greatly reduced fat deposition in the liver. Leptin therapy may have a role to play in preventing patients with lipodystrophy developing end-stage liver disease or in rescuing such patients who develop disease recurrence postliver transplantation.

HepatologyVolume 58, Issue 6 p. 2205-2206 Clinical Observations in HepatologyFree Access Recurrence of hepatopulmonary syndrome post–orthotopic liver transplantation in a patient with noncirrhotic portal hypertension Stephen Casey, Corresponding Author Stephen Casey Liver Transplant Unit, Austin Health, Heidelberg, Victoria, AustraliaAddress reprint requests to: Stephen Casey, Austin Health, Liver transplant unit, 145 Studley Road, Heidelberg, Melbourne, Victoria, Australia 3084. E-mail: stephen.casey@austin.org.au.Search for more papers by this authorAnthony Schelleman, Anthony Schelleman Radiology Department, Austin Health, Heidelberg, Victoria, AustraliaSearch for more papers by this authorPeter Angus, Peter Angus Liver Transplant Unit, Austin Health, Heidelberg, Victoria, AustraliaSearch for more papers by this author Stephen Casey, Corresponding Author Stephen Casey Liver Transplant Unit, Austin Health, Heidelberg, Victoria, AustraliaAddress reprint requests to: Stephen Casey, Austin Health, Liver transplant unit, 145 Studley Road, Heidelberg, Melbourne, Victoria, Australia 3084. E-mail: stephen.casey@austin.org.au.Search for more papers by this authorAnthony Schelleman, Anthony Schelleman Radiology Department, Austin Health, Heidelberg, Victoria, AustraliaSearch for more papers by this authorPeter Angus, Peter Angus Liver Transplant Unit, Austin Health, Heidelberg, Victoria, AustraliaSearch for more papers by this author First published: 31 July 2013 https://doi.org/10.1002/hep.26632Citations: 15 Potential conflict of interest: Nothing to report. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abbreviations HPS hepatopulmonary syndrome NCPH noncirrhotic portal hypertension OLT orthotopic liver transplantation. A 34-year-old Malaysian man presented with esophageal variceal bleeding, which was successfully treated with sclerotherapy. Investigations at that time showed evidence of portal hypertension with prominent portosystemic collateral vessels and splenomegaly. Hepatic synthetic function was normal. A liver biopsy revealed minimal fibrosis of nonspecific etiology and a diagnosis of noncirrhotic portal hypertension (NCPH) was made. Five years later he presented with increasing exertional breathlessness. On examination he had developed finger clubbing and was cyanotic. O2 saturation and PaO2 on room air were reduced at 91% and 60 mmHg, respectively. The PO2 rose to 576 mmHg on 100% O2. Pulmonary angiography showed no evidence of discrete AV malformations; however, hepatic vein wedge pressure was measured at the time and was elevated at 30 mmHg, in keeping with marked portal hypertension. Doppler studies of the hepatic vasculature showed patent vasculature. A repeat liver biopsy revealed hepatoportal sclerosis, in keeping with the original diagnosis of NCPH. Subsequently, a contrast-enhanced echocardiogram was performed which demonstrated delayed appearance of echo-contrast in the left atrium indicating an intrapulmonary shunt confirming the diagnosis of hepatopulmonary syndrome (HPS). The patient's respiratory symptoms insidiously worsened. By 4 years later his PaO2 on room air had fallen to 49 mmHg. A technetium-labeled macroaggregated albumin (99mTcMAA) lung perfusion scan revealed markedly abnormal brain uptake of radioactivity tracer and a shunt fraction of 15.25% (normal <6%) was calculated using standard methods.1 The patient was listed for orthotopic liver transplantation (OLT) and the surgery was successfully performed 6 months later. Examination of the explanted liver was again consistent with hepatoportal sclerosis with no evidence of cirrhosis or active liver disease. Following OLT his breathlessness improved steadily over several months. By 3 months post-OLT his O2 saturation on room air was 96% and PO2 was 90 mmHg. Three years post-OLT he presented with right upper quadrant discomfort and worsening dyspnea associated with the redevelopment of hypoxia. At rest, in the supine position his O2 saturation on room air was 93% with a PaO2 of 64 mmHg. A liver biopsy revealed no evidence of significant graft pathology and a computed tomography (CT) chest was unremarkable. A 99mTcMAA lung perfusion scan was repeated and indicated 8.9% brain uptake of tracer1 in keeping with recurrence of HPS (Fig. 1A). Given his abdominal discomfort and an abnormal hepatic Doppler study, he proceeded to an abdominal angiogram, which revealed a severe stenosis between the donor and recipient cava with minimal hepatic venous (HV) outflow (Fig. 2). The intercaval anastomosis was crossed with a guide wire and a balloon dilatation to 8 mm was performed resulting in markedly improved hepatic venous outflow (Fig. 3). Two months later the patient's dyspnea had completely resolved and PaO2 on room air had risen to 89 mmHg (Fig. 4). A repeat 99mTcMAA lung perfusion scan (Fig. 1B) revealed no significant brain uptake and thus confirmed resolution of HPS. Figure 1Open in figure viewerPowerPoint (A) 99TcMAA lung perfusion scan showing extrapulmonary tracer uptake in the brain (arrows). (B) Resolution of extrapulmonary tracer uptake after restoration of hepatic venous outflow. Figure 2Open in figure viewerPowerPoint Hepatic venous outflow obstruction (arrow) seen on hepatic venogram. Figure 3Open in figure viewerPowerPoint Restoration of hepatic venous outflow (arrow) after balloon dilatation was performed. Figure 4Open in figure viewerPowerPoint Changes in oxygenation in relation to clinical events. To our knowledge, the recurrence of HPS in an adult NCPH patient post-OLT has not been reported. HPS has been reported to recur posttransplantation in the context of serious graft disease or cirrhosis.2 In our case it redeveloped in the absence of any evidence of graft damage, suggesting that the hemodynamic alterations associated with impairment of hepatic outflow were solely responsible. While HV outlet obstruction is an unusual cause of HPS, the syndrome has been described in individuals with IVC obstruction with amelioration of hypoxia on restoration of flow.3 Why the disease occurs in only a minority of cirrhosis patients and only occasionally in patients with NCPH is uncertain. However, this presumably reflects an underlying "susceptibility" in those who develop the syndrome which is absent in most patients. What factors govern this susceptibility is as yet unknown. The redevelopment of clinically significant HPS in our patient many years posttransplant after apparent complete resolution of the syndrome shows that this susceptibility persists for life and that it cannot be related to liver disease per se or some host susceptibility factor within the liver. References 1Abrams GA, Nanda NC, Dubovsky EV, Krowka MJ, Fallon MB. Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: a new approach. Gastroenterology 1998; 114: 305- 310. CrossrefCASPubMedWeb of Science®Google Scholar 2Krowka MJ, Wiseman GA, Steers JL, Wiesner RH. Late recurrence and rapid evolution of severe hepatopulmonary syndrome after liver transplantation. Liver Transplant Surg 1999; 5: 451- 453. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 3De BK, Sen S, Biswas PK, Bandyopadhyay K, Das D, Das U, et al. Occurrence of hepatopulmonary syndrome in Budd-Chiari syndrome and the role of venous decompression. Gastroenterology 2002; 122: 897- 903. CrossrefPubMedWeb of Science®Google Scholar Citing Literature Volume58, Issue6December 2013Pages 2205-2206 This article also appears in:Clinical Observations in Hepatology FiguresReferencesRelatedInformation

BACKGROUND:Type 2 diabetes mellitus (T2DM) is a major risk factor for the development of non-alcoholic fatty liver disease (NAFLD) and subsequently hepatic fibrosis. Transient elastography (TE) is a rapid, reproducible non-invasive test that may be appropriate as a screening tool for the presence of hepatic fibrosis.AIM:Assess the utility of TE as a screening tool for the presence of hepatic fibrosis in a T2DM population with no known liver disease.METHODS:T2DM patients without known liver disease were included. Patients were assessed with TE in addition to biochemical parameters.RESULTS:A successful TE evaluation could be obtained in 74 of 81 (91%) included subjects. Of these, 26 (35%) had a liver stiffness measurement (LSM) ≥ 7.65 kPa. Sixteen of these subjects had confirmatory liver biopsies with significant (≥ F2 fibrosis) present in 12 (75%) and cirrhosis diagnosed in 2 subjects. 15/16 (94%) had histological steatohepatitis. Compared with those with a lower LSM, subjects with an LSM ≥ 7.65 kPa had higher ALT levels (38.0 ± 21.7 vs 26.1 ± 11.1 U/L, p = 0.021) and increased prevalence of hepatic steatosis by ultrasound (85% vs 63%, p = 0.005).CONCLUSION:Significant hepatic fibrosis in the T2DM population is frequently under-recognized. TE may be a feasible tool for the screening of T2DM patients for the presence of hepatic fibrosis.