Angiogenesis contributes to the development of nonalcoholic steatohepatitis (NASH) and promotes inflammation, fibrosis, and progression to hepatocellular carcinoma (HCC). Angiopoietin‐2 (Ang‐2) is a key regulator of angiogenesis. We aimed to investigate the role of Ang‐2 and its potential as a therapeutic target in NASH using human samples, in vivo mouse models, and in vitro assays. Serum Ang‐2 levels were determined in 104 obese patients undergoing bariatric surgery and concomitant liver biopsy. The effect of the Ang‐2/Tie2 receptor inhibiting peptibody L1‐10 was evaluated in the methionine‐choline deficient (MCD) and streptozotocin‐western diet nonalcoholic fatty liver disease mouse models, and in vitro on endothelial cells and bone marrow–derived macrophages. The hepatic vasculature was visualized with µCT scans and scanning electron microscopy of vascular casts. Serum Ang‐2 levels were increased in patients with histological NASH compared with patients with simple steatosis and correlated with hepatic CD34 immunoreactivity as a marker of hepatic angiogenesis. Serum and hepatic Ang‐2 levels were similarly increased in mice with steatohepatitis. Both preventive and therapeutic L1‐10 treatment reduced hepatocyte ballooning and fibrosis in MCD diet‐fed mice and was associated with reduced hepatic angiogenesis and normalization of the vascular micro‐architecture. Liver‐isolated endothelial cells and monocytes from MCD‐fed L1‐10–treated mice showed reduced expression of leukocyte adhesion and inflammatory markers, respectively, compared with cells from untreated MCD diet‐fed mice. In the streptozotocin‐western diet model, therapeutic Ang‐2 inhibition was able to reverse NASH and attenuate HCC progression. In vitro, L1‐10 treatment mitigated increased cytokine production in lipopolysaccharide‐stimulated endothelial cells but not in macrophages. Conclusion: Our findings provide evidence for Ang‐2 inhibition as a therapeutic strategy to target pathological angiogenesis in NASH.

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Portopulmonary hypertension (POPH), a complication of chronic liver disease, may be a contraindication to liver transplantation (LT) because of the elevated risk of peritransplant and posttransplant morbidity and mortality. Because POPH is frequently asymptomatic, screening with echocardiography is recommended. The only reliable technique, however, for diagnosing POPH is right heart catheterization (RHC). The aims of this study were to evaluate the current estimated systolic pulmonary artery pressure (sPAP) cutoff value of 30 mm Hg and to determine a better cutoff value. One hundred fifty-two patients underwent pretransplant echocardiography between January 2005 and December 2010. These echocardiographic results were compared with pulmonary artery pressures measured during the pretransplant workup or at the beginning of the transplantation procedure (both by catheterization). With a cutoff value of 30 mm Hg, 74 of the 152 patients met the criteria for POPH on echocardiography, although the diagnosis was confirmed in only 7 patients during catheterization; this resulted in a specificity of 54%. It would have been more accurate to use a cutoff value of 38 mm Hg, which had a maximal specificity of 82% and, at the same time, guaranteed a sensitivity and negative predictive value of 100%. With the incorporation of the presence or absence of right ventricular dilatation, the specificity even increased to 93% for this new cutoff value. In conclusion, the prevalence of POPH was 4.6% among LT candidates in this study. We can recommend that LT candidates with an sPAP > 38 mm Hg should be referred for RHC. With the cutoff value increased from 30 to 38 mm Hg, the number of patients undergoing invasive RHC during their evaluation could be safely reduced. Liver Transpl 19:602-610, 2013. V C 2013 AASLD.Received November 11, 2012; accepted February 27, 2013. See Editorial on Page 573Portopulmonary hypertension (POPH), the presence of pulmonary hypertension in association with portal hypertension, is a known complication of chronic liver disease.1-9 Prospective studies and case-control studies have documented that POPH occurs in approximately 5% to 6% of patients with advanced liver disease. 5 In patients with portal hypertension, the association with pulmonary hypertension is seen in 2% to 6%.10,11 The incidence of POPH in patients referred for liver transplantation (LT) is 4% to 6%. 12Abbreviations: CO, cardiac output; LT, liver transplantation; mPAP, mean pulmonary artery pressure; mRAP, mean right atrial pressure; NA, not applicable; ND, not determined; NS, not significant; PCWP, pulmonary capillary wedge pressure; POPH, portopulmonary hypertension; PVR, pulmonary vascular resistance; RHC, right heart catheterization; RVEDD, right ventricular end-diastolic diameter; sPAP, systolic pulmonary artery pressure; SVR, systemic vascular resistance; TPG, transpulmonary gradient.

CBDL in mice induces HPS, which is mediated by PlGF production; αPlGF treatment improves experimental HPS by counteracting pulmonary angiogenesis and might be an attractive therapeutic strategy for human HPS. (Hepatology 2017).

Keywords hepatopulmonary syndrome -liver diseaseportopulmonary hypertension Abbreviations Akt, protein kinase B; BMPR2, bone morphogenetic protein receptor type II; CBDL, common bile duct ligation; CO, carbon monoxide; CX3CL1, chemokine ligand 1, chemokine fractalkine; CX3CR1, chemokine receptor 1, chemokine fractalkine receptor; eNOS, endothelial nitric oxide synthase; ERK, extracellular-signal-regulated kinase; ET-1, endothelin-1; ETR, endothelin receptor; FiO 2 , fraction of inspired oxygen; GRP78, glucoseregulated protein 78; HO, haem oxygenase; GMP, guanosine monophosphate; HPS, hepatopulmonary syndrome; iNOS, inducible nitric oxide synthase; IPVD, intrapulmonary vascular dilation; L-NAME, nebulized NGAbstract Hepatopulmonary syndrome and portopulmonary hypertension are cardiopulmonary complications, which are not infrequently seen in patients with liver disease and/or portal hypertension. These entities are both clinically and pathophysiologically different: the hepatopulmonary syndrome is characterized by abnormal pulmonary vasodilation and right-to-left shunting resulting in gas exchange abnormalities, whereas portopulmonary hypertension is caused by pulmonary artery vasoconstriction leading to hemodynamic failure. As both hepatopulmonary syndrome and portopulmonary hypertension are associated with significantly increased morbidity and mortality, and as these patients are commonly asymptomatic, all liver transplantation candidates should be actively screened for the presence of these two complications. The aim of is this review is to provide an overview on the hepatopulmonary syndrome and portopulmonary hypertension with primary focus on diagnosis and recent knowledge regarding pathogenesis and therapeutic targets.nitro-L-arginine methyl ester; LT, liver transplantation; MAA scan, 99 mTechnetium-labelled macroaggregated albumin scan; MAPK, mitogen-activated protein kinase; mPAP, mean pulmonary artery pressure; mRAP, mean right atrial pressure; MTTE, microbubble transthoracic echocardiography; NO, nitric monoxide; P(A-a) O 2 gradient alveolar-arterial oxygen gradient; PaCO 2 , arterial carbon dioxide tension; PAH, pulmonary artery hypertension; PaO 2 , arterial oxygen tension; PCWP, pulmonary capillary wedge pressure; PDE-5, phosphodiesterase type 5; PI3K, phosphoinositide 3