Angiogenesis and disruption of liver vascular architecture have been linked to progression to cirrhosis and liver cancer (HCC) in chronic liver diseases, which contributes both to increased hepatic vascular resistance and portal hypertension and to decreased hepatocyte perfusion. On the other hand, recent evidence shows that angiogenesis modulates the formation of portal-systemic collaterals and the increased splanchnic blood flow which are involved in the life threatening complications of cirrhosis. Finally, angiogenesis plays a key role in the growth of tumours, suggesting that interference with angiogenesis may prevent or delay the development of HCC. This review summarizes current knowledge on the molecular mechanisms of liver angiogenesis and on the consequences of angiogenesis in chronic liver disease. On the other hand, it presents the different strategies that have been used in experimental models to counteract excessive angiogenesis and its potential role in preventing transition to cirrhosis, development of portal hypertension and its consequences, and its application in the treatment of hepatocellular carcinoma.

Every year almost 500,000 new patients are diagnosed with hepatocellular carcinoma (HCC), a primary malignancy of the liver that is associated with a poor prognosis. Numerous experimental models have been developed to define the pathogenesis of HCC and to test novel drug candidates. This review analyses several mouse models useful for HCC research and points out their advantages and weaknesses. Chemically induced HCC mice models mimic the injury-fibrosis-malignancy cycle by administration of a genotoxic compound alone or, if necessary, followed by a promoting agent. Xenograft models develop HCC by implanting hepatoma cell lines in mice, either ectopically or orthotopically; these models are suitable for drug screening, although extrapolation should be considered with caution as multiple cell lines must always be used. The hollow fibre assay offers a solution for limiting the number of test animals in xenograft research because of the ability for implanting multiple cell lines in one mouse. There is also a broad range of genetically modified mice engineered to investigate the pathophysiology of HCC. Transgenic mice expressing viral genes, oncogenes and/or growth factors allow the identification of pathways involved in hepatocarcinogenesis

Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.

Graft hyperperfusion in small-for-size grafts (SFSG) is considered the main causal factor of small-for-size syndrome (SFSS). We compared SFSG with a graft-torecipient body ratio ≤0.8, with and without graft inflow modulation (GIM) by means of a hemi-portocaval shunt (HPCS). Thirteen patients underwent adult-toadult living donor liver transplantation (AALDLT): G1, n = 5 [4 right livers (RL) and 1 left liver (LL)] without GIM, and G2, n = 8 (4 RL and 4 LL) with GIM. In G2 patients, portal vein flow (PVF) was significantly reduced by HPCS: 190 ± 70 mL/min/100 g liver in G2 vs. 401 ± 225 ml/min in G1 (p = 0.002). One-and 6-month post-transplantation graft volume/standard liver volume (GV/SLV) ratio was of 72% and 79.5% in G1; 80% and 101% in G2 (p = ns). SFSS was observed in three G1 recipients (who were retransplanted), but in none of the G2 patients. At 1-year, patient and graft survival was respectively of 40% and 20% in G1, 87.5% and 75% in G2 (p = 0.024 and 0.03).It is concluded that drastic reduction of PVF by means of HPCS improves overall patient and graft survival by averting the occurrence of SFSS. Graft inflow modulation through HPCS reduces the risk of complications when transplanting SFSG in adult recipients.

Portopulmonary hypertension represents a major risk factor for transplantation; therefore, preoperative detection is crucial. The aims of this study were to determine (1) whether Doppler echocardiography performed at evaluation is a reliable tool for detecting portopulmonary hypertension and (2) the incidence of acquired portopulmonary hypertension profile after evaluation. One hundred sixty-five patients had Doppler echocardiography and right heart catheterization at evaluation over a 9-year period. All patients had a prospective follow-up, and the results of catheterization at evaluation were compared with those obtained at the time of transplantation. Seventeen of 165 patients met the criteria for portopulmonary hypertension on Doppler echocardiography. Portopulmonary hypertension was confirmed by catheterization in 10 patients and ruled out in 7. There were no false negatives for echocardiography. Mean pulmonary artery pressure was significantly higher during the initial phase of transplantation than at evaluation (17.8 ؎ 4.3 vs. 20.3 ؎ 5.5 mm Hg, respectively, P < .0001), and there was no significant correlation between values obtained at these 2 time points. Three patients showed to have acquired portopulmonary hypertension profile while waiting for a graft within time intervals ranging from 2.5 to 5 months. In conclusion, Doppler echocardiography is a highly sensitive tool for detecting portopulmonary hypertension. However, because this technique has a poor positive predictive value, right heart catheterization is recommended for confirming portopulmonary hypertension. In addition, the absence of portopulmonary hypertension at evaluation does not exclude the occasional occurrence of acquired portopulmonary hypertension profile after listing. P ulmonary hypertension associated with portal hypertension, the so-called portopulmonary hypertension, is a rare complication of cirrhosis. When severe, this condition is a major risk factor for transplantation because, in most cases, patients are at best partially responsive to medical therapies. 1 If it is impossible to lower mean pulmonary artery pressure below 40 to 50 mm Hg during transplantation procedure, any significant hemodynamic changes, such as those observed at the time of caval clamping and reperfusion of the graft, may result in irreversible cardiac arrest, especially if right ventricular function is impaired. 2 As a consequence, many authors consider that severe portopulmonary hypertension (i.e., mean pulmonary artery pressure [MPAP] above 40 mm Hg) represents a contraindication for liver transplantation because it would carry an unacceptable mortality rate. 3 Because portopulmonary hypertension is frequently asymptomatic until mean pulmonary pressure exceeds 40 mm Hg, most authors recommend systematic screening at evaluation. Several studies have suggested that Doppler echocardiography, when performed during pretransplantation evaluation, is a useful noninvasive tool to document or exclude portopulmonary hypertension, 4-6 even though this technique ...

Nowadays, liver cancer, cirrhosis and other liver-related diseases are the fifth most common cause of mortality in the UK. Furthermore, chronic liver diseases (CLDs) are one of the major causes of death, which are still increasing year-on-year. Therefore, knowledge about the pathophysiology of CLDs and its complications is of uttermost importance. The goal of this review is to clarify the role of angiogenesis in the disease progression of various liver diseases. Looking closer at the pathophysiology of portal hypertension (PH), fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), we find that angiogenesis is a recurring factor in the disease progression. In PH, several factors involved in its pathogenesis, such as hypoxia, oxidative stress, inflammation and shear stress are potential mediators for the angiogenic response. The progression from fibrosis to cirrhosis, the end-point of CLDs, is distinguished by a prolonged inflammatory and fibrogenic process that leads to an abnormal angioarchitecture distinctive for cirrhosis. In several stages of NASH, a link might be made between the disease progression and hepatic microvasculature changes. HCC is one of the most vascular solid tumours in which angiogenesis plays an important role in its development, progression and metastasis. The close relationship between the progression of CLDs and angiogenesis emphasises the need for anti-angiogenic therapy as a tool for blocking or slowing down the disease progression. The fact that angiogenesis plays a pivotal role in CLDs gives rise to new opportunities for treating CLDs and its complications.

When a suboptimal graft:recipient body weight ratio is accompanied by high rPVF in ALDLTx, the portal flow should be modulated perioperatively; splenic artery ligation is a simple and safe method that is sufficient to allow this modulation in most patients.

Wait-listed (n ϭ 226) or post-liver transplantation (n ϭ 241) chronic hepatitis B (CHB) patients with lamivudine-resistant hepatitis B virus (HBV) were treated with adefovir dipivoxil for a median of 39 and 99 weeks, respectively. Among wait-listed patients, serum HBV DNA levels became undetectable (Ͻ1,000 copies/mL) in 59% and 65% at weeks 48 and 96, respectively. After 48 weeks, alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 77%, 76%, 60%, and 84% of wait-listed patients, respectively. Among posttransplantation patients, serum HBV DNA levels became undetectable in 40% and 65% at weeks 48 and 96, respectively. After 48 weeks, ALT, albumin, bilirubin, and prothrombin time normalized in 51%, 81%, 76%, and 56% of posttransplantation patients, respectively. Among wait-listed patients who underwent on-study liver transplantation, protection from graft reinfection over a median of 35 weeks was similar among patients who did (n ϭ 34) or did not (n ϭ 23) receive hepatitis B immunoglobulin (HBIg). Hepatitis B surface antigen was detected on the first measurement only in 6% and 9% of patients who did or did not receive HBIg, respectively. Serum HBV DNA was detected on consecutive visits in 6% and 0% of patients who did or did not receive HBIg, respectively. Treatment-related adverse events led to discontinuation of adefovir dipivoxil in 4% of patients. Cumulative probabilities of resistance were 0%, 2%, and 2% at weeks 48, 96, and 144, respectively. In conclusion, adefovir dipivoxil is effective and safe in wait-listed or posttransplantation CHB patients with lamivudine-resistant HBV and prevents graft reinfection with or without HBIg. Liver Transpl 13:349-360, 2007.