Target‐organ protection with combination renin‐angiotensin‐system blockade

Pharmacologic blockade of the renin‐angiotensin‐aldosterone system (RAS) has antihypertensive, anti‐atherogenic, antioxidant, and anti‐inflammatory effects. Treatment with angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been demonstrated to prevent atrial fibrillation and new‐onset diabetes, and provide cardiac, cerebral, and renal protection. Combination therapy with ACEIs and ARBs, compared with monotherapy, provides enhanced reno‐ and cardioprotection, although available data indicate that combination RAS blockade may be beneficial only in select patient groups, such as those with diabetes mellitus, chronic kidney disease, or heart failure (HF). In certain high‐risk patients, the use of ARBs provides comparable efficacy to that observed with ACEIs. The efficacy of these agents may stem from pleiotropic effects beyond blood pressure (BP) reduction. Several studies demonstrate achievement of clinical endpoints without significant effects on BP. Copyright © 2009 Wiley Periodicals, Inc.     

The effect of angiotensin‐blocking agents on liver fibrosis in patients with hepatitis C

Background: Multiple studies implicate the renin–angiotensin system in hepatic fibrogenesis. Few studies have examined the effects of angiotensin blockade on liver fibrosis via human histology. Aims: We studied the histological effect of angiotensin II blocking agents in chronic hepatitis C patients. Methods: This was a retrospective study of 284 chronic hepatitis C patients from 2001 to 2006 who underwent a liver biopsy. Group I was comprised of 143 hypertensive patients who received angiotensin‐blocking agents. Group II was comprised of 91 hypertensive subjects who received hypertensive agents other than angiotensin blockers. Group III was comprised of 50 non‐hypertensive subjects. Results: The groups were similar in age, sex, hepatitis C genotype, viral load and disease duration. They varied significantly in total diabetic patients (Group I, 43; Group II, 10; Group III, 1; P=0.0001), consistent with recommended use of angiotensin‐converting enzyme inhibitors in hypertensive diabetics. Non‐hypertensive patients had significantly less fibrosis than hypertensive patients, regardless of antihypertensive medications (Group I, 3.20; Group II, 3.73; Group III, 2.5; P=0.0002). Group I had significantly less fibrosis than Group II (P=0.02). This finding persisted in a non‐diabetic subgroup of Groups I and II (Group I, 3.07; Group II, 3.69; P=0.0129). Conclusion: Patients with hepatitis C and hypertension have increased fibrosis compared with non‐hypertensive patients. Hypertensive patients receiving angiotensin‐blocking agents had less fibrosis than hypertensive patients who did not receive angiotensin‐blocking agents. This suggests an association with hypertension, possibly via the renin–angiotensin system in the fibrosis development and suggests a beneficial role of angiotensin II blockade in hepatitis C virus‐related fibrosis.     

Effect of granulocyte-macrophage colony-stimulating factor on hepatic regeneration after 70% hepatectomy in normal and cirrhotic rats

BackgroundPost-hepatectomy liver insufficiency is one of the most serious postoperative problems and its prevention is important after major hepatic resection, especially in the cirrhotic liver. Some growth factors and cytokines appear to play important roles in liver regeneration. In the present study we have investigated the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on hepatic regeneration after 70% partial hepatectomy (PH) in cirrhotic and non-cirrhotic rats.MethodsA rat model of liver cirrhosis was prepared using thioacetamide (TAA) (a dose of 20 mg/100 g body w, intra-peritoneally) on three days a week for 12 weeks. Adult male rats were divided into four groups:Group 1 (n=10) no cirrhosis and no GM-CSF; Group 2 (n=10) no cirrhosis and GM-CSF; Group 3 (n=10) cirrhosis and no GM-CSF; and Group 4 (n=10) cirrhosis and GM-CSF. All the rats underwent a 70% hepatectomy, and GM-CSF was administrated immediately after operation in Groups 2 and 4. On postoperative days 2 and 7, fresh samples from the remnant liver were obtained to evaluate its regenerative capacity.The liver regenerative process was estimated by DNA synthesis, using flow cytometry.ResultsProliferation index (PI) of hepatocytes at 48 h was higher in Group 4 rats than Group 3 rats (p<0.05). On postoperative day 7, PI was elevated in Group 3 rats compared with Group 4 rats, but this difference was not statistically significant. In non-cirrhotic rats given GM-CSF, PI was increased compared with Group 1 rats at day 2 (p<0.05), but not at day 7.ConclusionsThe findings suggest that the proliferative capacity of liver cells is impaired and delayed after 70% PH in cirrhotic rat liver. GM-CSF administration might enhance the liver PI in both normal and TAA-induced cirrhotic rats.     

Parenchymal transection with ultrasonic scalpel in liver resection

BackgroundThere is no ideal tool for parenchymal transection in liver resection and bleeding is still a major complication. The purpose of this study was to evaluate the usefulness of an ultrasonic scalpel and to describe our clinical experience in open liver resection.MethodsAn ultrasonic scalpel was used in seven consecutive patients undergoing liver resection. During parenchymal transection coagulation shears were used with the power level set at 2 or 3, and the blunt blades were selected.ResultsIn each case, bleeding from the liver parenchyma was trivial, but haemostasis of large vessels required suture ligation. Postoperatively none of the patients experienced local technical complications such as haematoma, bile leak or infection.DiscussionAlthough complete haemostasis of large vessels cannot be achieved, the ultrasonic scalpel may be used for parenchymal transection in liver resection to reduce blood loss. Larger series of patients are needed before a definitive statement regarding the efficacy of this method can be made.     

The influence of spleen size on liver regeneration after major hepatectomy in normal and early cirrhotic liver.

BACKGROUND/PURPOSE: The relationship between liver regeneration and spleen size after major hepatectomy in normal and cirrhotic liver was studied by single photon emission computed tomography (SPECT). MATERIALS AND METHODS: Twenty-six patients, 18 patients with normal liver and eight patients with cirrhotic liver, receiving major hepatectomy were included. Liver and spleen volumes were measured by SPECT before major hepatectomy, 6 months, 1 year and 2 years after operation. The correlation of liver and spleen volume during liver regeneration was analyzed. RESULTS: In both groups, the residual liver volume increased within the first year and decreased in the second year. No difference in regeneration ability was found. The spleen volume in cirrhotic liver was increased, with a trend similar to normal liver during the first year. In contrast, the increased spleen volume persisted up to the second year in cirrhotic patients. Age per year, the female sex, and body surface index had a positive correlation with increased percentage of liver volume. The spleen volume per 100 ml with time played a significantly negative role in increasing percentage of liver volume, confidence interval: -2.16 to -27.92, P=0.011. CONCLUSION: In early cirrhotic liver within normal functional limits, the liver still could regenerate as a normal liver after major hepatectomy in 1 year. Age, the female sex, and body surface index had positive correlation but the size of spleen volume played a negative role to regenerative liver volume.     

Cloning of the rat ADAMTS‐1 gene and its down regulation in endothelial cells in cirrhotic rats

Abstract: Aims: This study was undertaken in order to identify genes which are regulated during the process of liver fibrosis. Methods: The differential display method and RNA from rat endothelial cells before and after induction of cirrhosis were used. Results: A 496bp fragment, which was down regulated in liver endothelial cells from a cirrhotic animal, was cloned. The cloned fragment showed a 95% homology with the newly cloned mouse ADAMTS‐1 gene (a disintegrin and metalloproteinase with thrombospondin motifs), which is implicated in inflammation. The fragment was found to span the 3′ of exon 6, the whole exon 7 and the 5′ of exon 8. Sequencing of the entire coding region of the rat gene showed a 94% homology at the nucleic acid level and 96% homology at the amino acid level. The sequences responsible for the function of the protein were conserved. Northern blot analysis, using the cloned fragment as a probe, confirmed the finding that the gene was down‐regulated in endothelial cells derived from livers of cirrhotic animals. In situ PCR analysis localised the ADAMTS‐1 gene in the liver endothelial cells from normal animals. Conclusions: Regulation of the expression of genes which belong to the metalloproteinase family in liver endothelial cells might be important in the development of liver cirrhosis.     

Meta‐analysis of simultaneous versus staged resection for synchronous colorectal liver metastases

Aim: There is no clear consensus on the optimal timing of surgical resection for synchronous colorectal liver metastases (SCLM). This study is a meta‐analysis of the available evidence. Methods: Systematic review and meta‐analysis of trials comparing outcomes following simultaneous resection with staged resection for SCLM published from 1990 to 2010 in PubMed, Embase, Ovid and Medline. Pooled odds ratios (OR) or weighted mean differences (WMD) with 95% confidence intervals (95% CI) were calculated using either the fixed effects or random effects model. Results: Nineteen non‐randomized controlled trials (NRCT) studies were included in this analysis. These studies included a total of 2724 patients: 1116 underwent simultaneous resection and 1608 underwent staged resection. Meta‐analysis showed that shorter hospital stay (P < 0.001) and lower total complication rate (P < 0.001) were observed in patients undergoing simultaneous resection group. The overall survival rate in the simultaneous resection group did not statistically differ with that in the staged resection group at 1 year (P = 0.13), 3 years (P = 0.26), 5 years (P = 0.38), as well as the 1, 3 and 5 years disease‐free survival rates (respectively, P = 0.55; P = 0.16; P = 0.12). No significant difference was noted between the two groups in terms of mortality (P = 0.16), intraoperative blood loss (P = 0.06) and recurrence (P = 0.47). Conclusion: Simultaneous resection is safe and efficient in the treatment of patients with SCLM while avoiding a second laparotomy. In selected patients, simultaneous resection might be considered as the preferred approach. However, the findings have to be carefully interpreted due to the lower level of evidence and the existence of heterogeneity.     

Cardiotrophin‐1 enhances regeneration of cirrhotic liver remnant after hepatectomy through promotion of angiogenesis and cell proliferation

Background/Aim: Hepatic resection is not applicable to a certain proportion of hepatocellular carcinoma patients owing to an insufficient liver function reserve. The present study was designed to investigate the effects of cardiotrophin‐1 (CT‐1) on improving the function of CCl₄‐induced cirrhotic liver remnant after major hepatectomy. Methods: CT‐1 was administered to rats after hepatectomy according to different protocols. Results: A double‐dose CT‐1 protocol improved liver function, enlarged the volume of liver remnant, upregulated the expression of von Willebrand factor and increased the number of BrdU⁺ or Ki‐67⁺ hepatocytes. Administration of CT‐1 enhanced the expression of nuclear factor‐κB (P65), vascular endothelial growth factor (VEGF), CyclinD1 and p42/44 in the liver remnant. However, the effects of CT‐1 were blocked by a VEGF receptor blocker, PTK787. Although the expression of gp130, a receptor of CT‐1, was downregulated in the diseased hepatocytes isolated from the cirrhotic liver, CT‐1 could still stimulate the cell proliferation. CT‐1 administration enhanced the expression of P65 and VEGF in the diseased hepatocytes, but the augmented P65 and VEGF expression was blocked by PTK787 administration. Conclusion: Short‐term administration of CT‐1 could improve the function of cirrhotic liver remnant and stimulate liver regeneration through promotion of angiogenesis and cell proliferation.     

Resecting hepatocellular carcinoma in cirrhotic liver

Abstract   Resecting hepatocellular carcinoma (HCC) in a cirrhotic patient is potentially dangerous and recurrence of HCC after operation is high. Our current strategy consists of careful preoperative assessment of liver functions by indocyanine green clearance test, intraoperative techniques to reduce blood loss, and postoperative surveillance and prompt treatment of recurrences. The 5-year overall survival rate of HCC patients after resection is 34.3%, which is comparable with that in patients with normal liver (37.3%) or chronic hepatitis (45.3%).     

A distinct nitric oxide and adenosine A1 receptor dependent hepatic artery vasodilatatory response in the CCl4‐cirrhotic liver

Increase of portal venous vascular resistance is counteracted by decrease of hepatic arterial vascular resistance (hepatic arterial buffer response). This process is mediated by adenosine in normal livers. In cirrhosis, hepatic arterial vascular resistance is decreased but the involvement of adenosine in this process is unknown. The aim of our study was to identify the signalling pathway responsible for the decreased hepatic arterial resistance in cirrhotic livers. Methods: Cirrhosis was induced by CCl₄. Using a bivascular liver perfusion dose–response curves to adenosine of the HA were performed in the presence and the absence of pan‐adenosine blocker (8‐SPT), A1 blocker (caffeine) or nitric oxide synthase‐blocker (l ‐NMMA) after preconstriction with an α1‐agonist (methoxamine). Western blot of the HA were used to measure the density of the A1 and A2a receptors. Results: Adenosine caused a dose dependent relaxation of the hepatic artery of both cirrhotic and control animals that were blocked in both groups by 8‐SPT (P<0.02). The response to adenosine was greater in cirrhotic rats (P=0.016). Both l ‐NMMA (P=0.003) and caffeine reduced the response to adenosine in cirrhotic but not in control animals. Western blot analysis showed a higher density of A1 and a lower density of A2a receptor in cirrhotic animals (P<0.05). Conclusion: The adenosine‐induced vasodilatation of the HA is increased in cirrhotic rats suggesting a role for adenosine‐NO in the decreased hepatic arterial vascular resistance found in cirrhosis. This significantly greater response in cirrhosis by the A1 receptor follows the same pathway that is seen in hypoxic conditions in extra‐hepatic tissues.