Pathological process of liver sinusoidal endothelial cells in liver diseases

Cirrhosis develops from liver fibrosis and is the severe pathological stage of all chronic liver injury. Cirrhosis caused by hepatitis B virus and hepatitis C virus infection is especially common. Liver fibrosis and cirrhosis involve excess production of extracellular matrix,which is closely related to liver sinusoidal endothelial cells(LSECs). Damaged LSECs can synthesize transforming growth factor-beta and platelet-derived growth factor,which activate hepatic stellate cells and facilitate the synthesis of extracellular matrix. Herein,we highlight the angiogenic cytokines of LSECs related to liver fibrosis and cirrhosis at different stages and focus on the formation and development of liver fibrosis and cirrhosis. Inhibition of LSEC angiogenesis and antiangiogenic therapy are described in detail. Targeting LSECs has high therapeutic potential for liver diseases. Further understanding of the mechanism of action will provide stronger evidence for the development of anti-LSEC drugs and new directions for diagnosis and treatment of liver diseases.

Ceruloplasmin, a reliable marker of fibrosis in chronic hepatitis B virus patients with normal or minimally raised alanine aminotransferase

AIM To develop a non-invasive model to evaluate significant fibrosis and cirrhosis by investigating the association between serum ceruloplasmin(CP) levels and liver fibrosis in chronic hepatitis B(CHB) patients with normal or minimally raised alanine aminotransferase(ALT).METHODS Serum samples and liver biopsy were obtained from 193 CHB patients with minimally raised or normal ALT who were randomly divided into a training group(n = 97) and a validation group(n = 96). Liver histology was evaluated by the METAVIR scoring system. Receiver operator characteristic curves were applied to the diagnostic value of CP for measuring liver fibrosis in CHB patients. Spearman rank correlation analyzed the relationship between CP and liver fibrosis. A noninvasive model was set up through multivariate logistic regression analysis.RESULTS Serum CP levels individualized various fibrosis stages via area under the curve(AUC) values. Multivariate analysis revealed that CP levels were significantlyrelated to liver cirrhosis. Combining CP with serum GGT levels, a CG model was set up to predict significant fibrosis and liver cirrhosis in CHB patients with normal or minimally raised ALT. The AUC, sensitivity, specificity, positive predictive value, and negative predictive value were 0.84, 83.1%, 78.6%, 39.6%, and 96.5% to predict liver cirrhosis, and 0.789, 80.26%, 68.38%, 62.25%, and 84.21% to predict significant fibrosis. This model expressed a higher AUC than FIB-4(age, ALT, aspartate aminotransferase, platelets) and GP(globulin, platelets) models to predict significant fibrosis(P = 0.019 and 0.022 respectively) and revealed a dramatically greater AUC than FIB-4(P = 0.033) to predict liver cirrhosis.CONCLUSION The present study showed that CP was independently and negatively associated with liver fibrosis. Furthermore, we developed a novel promising model(CG), based on routine serum markers, for predicting liver fibrosis in CHB patients with normal or minimally raised ALT.

Antioxidant and anti-inflammatory action of melatonin in an experimental model of secondary biliary cirrhosis induced by bile duct ligation

AIM To evaluate the effects of melatonin(Mel) on oxidative stress in an experimental model of bile duct ligation(BDL).METHODS Male Wistar rats(n = 32, weight ± 300 g) were allocated across four groups: CO(sham BDL), BDL(BDL surgery), CO + Mel(sham BDL and Mel administration) and BDL + Mel(BDL surgery and Mel administration). Mel was administered intraperitoneally for 2 wk, starting on postoperative day 15, at a dose of 20 mg/kg.RESULTS Mel was effective at the different standards, reestablishing normal liver enzyme levels, reducing the hepatosomatic and splenosomatic indices, restoring lipoperoxidation and antioxidant enzyme concentrations, reducing fibrosis and inflammation, and thereby reducing liver tissue injury in the treated animals.CONCLUSION The results of this study suggest a protective effect of Mel when administered to rats with secondary biliary cirrhosis induced by BDL.

Sampling variability of computer-aided fractal-corrected measures of liver fibrosis in needle biopsy specimens

AIM： TO assess the sampling variability of computeraided, fractal-corrected measures of fibrosis in liver biopsies. METHODS： Samples were derived from six to eight different parts of livers removed from 12 patients with clinically and histologically proven cirrhosis undergoing orthotopic liver transplantation. Sirius red-stained sections with a thickness of 2 μm were digitized using a computer-aided image analysis system that automatically measures the surface of fibrosis, as well as its outline perimeter, fractal surface and outline dimensions, wrinldedness, and Hurst coefficient. RESULTS： We found a high degree of inter-sample variability in the measurements of the surface [coefficient of variation （CV） = 43% ± 13%] and wrinkledness （CV = 28% ± 9%） of fibrosis, but the inter-sample variability of Hurst＇s exponent was low （CV = 14% ± 2%）. CONCLUSION： This study suggests that Hurst＇s exponent might be used in clinical practice as the best histological estimate of fibrosis in the whole organ, and evidences the fact that biopsy sections, which are fundamental for the qualitative diagnosis of chronic hepatitis, play a key role in the quantitative estimate of architectural changes in liver tissue.

Magnetic resonance elastography is accurate in detecting advanced fibrosis in autoimmune hepatitis

AIM To assess the value of magnetic resonance elastography (MRE) in detecting advanced fibrosis/cirrhosis in autoimmune hepatitis (AIH). METHODS In this retrospective study, 36 patients (19 treated and 17 untreated) with histologically confirmed AIH and liver biopsy performed within 3 mo of MRE were identified at a tertiary care referral center. Liver stiffness (LS) with MRE was calculated by a radiologist, and inflammation grade and fibrosis stage in liver biopsy was assessed by a pathologist in a blinded fashion. Two radiologists evaluated morphological features of cirrhosis on conventional magnetic resonance imaging (MRI). Accuracy of MRE was compared to laboratory markers and MRI for detection of advanced fibrosis/cirrhosis. RESULTS Liver fibrosis stages of 0, 1, 2, 3 and 4 were present in 4, 6, 7, 6 and 13 patients respectively. There were no significant differences in distribution of fibrosis stage and inflammation grade between treated and untreated patient groups. LS with MRE demonstrated stronger correlation with liver fibrosis stage in comparison to laboratory markers for chronic liver disease (r = 0.88 vs -0.48-0.70). A trend of decreased mean LS in treated patients compared to untreated patients was observed (3.7 kPa vs 3.84 kPa) but was not statistically significant. MRE had an accuracy/sensitivity/specificity/positive predictive value/negative predictive value of 0.97/90%/100%/100%/90% and 0.98/92.3%/96%/92.3%/96% for detection of advanced fibrosis and cirrhosis, respectively. The performance of MRE was significantly better than laboratory tests for detection of advanced fibrosis (0.97 vs 0.53-0.80, p < 0.01), and cirrhosis (0.98 vs 0.58-0.80, p < 0.01) and better than conventional MRI for diagnosis of cirrhosis (0.98 vs 0.78, p = 0.002). CONCLUSION MRE is a promising modality for detection of advanced fibrosis and cirrhosis in patients with AIH with superior diagnostic accuracy compared to laboratory assessment and MRI.

Serelaxin increases the antifibrotic action of rosiglitazone in a model of hepatic fibrosis

To determine the effect of combined serelaxin and rosiglitazone treatment on established hepatic fibrosis.METHODSHepatic fibrosis was induced in mice by carbon tetrachloride administration for 6 wk, or vehicle alone (nonfibrotic mice). For the final 2 wk, mice were treated with rosiglitazone, serelaxin, or both rosiglitazone and serelaxin. Serum liver enzymes and relaxin levels were determined by standard methods. The degree of liver collagen content was determined by histology and immunohistochemistry. Expression of type I collagen was determined by quantitative PCR. Activation of hepatic stellate cells was assessed by alpha-smooth muscle actin (SMA) levels. Liver peroxisome proliferator activated receptor-gamma coactivator 1 alpha (PGC1α) was determined by Western blotting.RESULTSTreatment of mice with CCl4 resulted in hepatic fibrosis as evidenced by increased liver enzyme levels (ALT and AST), and increased liver collagen and SMA. Monotherapy with either serelaxin or rosiglitazone for 2 wk was generally without effect. In contrast, the combination of serelaxin and rosiglitazone resulted in significantly improved ALT levels (P < 0.05). Total liver collagen content as determined by Sirius red staining revealed that only combination treatment was effective in reducing total liver collagen (P < 0.05). These results were supported by immunohistochemistry for type I collagen, in which only combination treatment reduced fibrillar collagen levels (P < 0.05). The level of hepatic stellate cell activation was modestly, but significantly, reduced by serelaxin treatment alone, but combination treatment resulted in significantly lower SMA levels. Finally, while hepatic fibrosis reduced liver PGC1α levels, the combination of serelaxin and rosiglitazone resulted in restoration of PGC1α protein levels.CONCLUSIONThe combination of serelaxin and rosiglitazone treatment for 2 wk was effective in significantly reducing established hepatic fibrosis, providing a potential new treatment strategy.

Is spleen circulation impaired in systemic sclerosis and what is the role of liver fibrosis?

AIM:To investigate the spleen vascular involvement and the presence of liver fibrosis in a population of subjects with established systemic sclerosis(SSc).METHODS:In a cross-sectional fashion,17 patients with SSc were compared with 18 patients suffering from hepatitis C virus(HCV) -related liver cirrhosis,grade A and B Child-Pugh classification.Eighteen non elderly subjects,apparently healthy,were used as the control group.Splenic artery resistivity index(SARI) at doppler ultraSound,transient elastography of liver and nailfold capillaroscopy were the main outcomes.RESULTS:Transient elastography values of SSc patients were similar to those of controls;5.2±1.1 vs 4.5 ±1,(P=0.07).Median Alanine amino transferase(ALT) concentrations of cirrhotic patients were greater than those of controls and SSc patients,i.e.66.5(36-89) U/L vs 29(22-34) U/L and 31(22-41) U/L,respectively,(P =0.005).SARI determinations in cirrhotic patients,although significantly higher than those found in controls and SSc patients,showed some degree of overlap with SSc patients,i.e.0.59 vs 0.52 and 0.57,respectively,(P =0.04).Mean systolic blood pressure was significantly higher in SSc patients than in cirrhotics and controls,i.e.142 mmHg vs 128.2 mmHg and 127 mmHg,respectively,(P=0.005).Mean diastolic blood pressure behaved in a similar fashion,i.e.84 mmHg vs 72.2 mmHg and 76.9 mmHg(P=0.005).Nailfold Capillaroscopy grades and diastolic blood pressure values correlated well with SARI results.CONCLUSION:An enhanced resistivity of the splenic artery was found in patients suffering from SSc;they did not have evidence of splenomegaly as well as no liver fibrosis or any other form of liver damage.

Impact of hepatitis C oral therapy in portal hypertension

Chronic hepatitis C is a leading cause of morbidity and mortality, mainly related to fibrosis/cirrhosis and portal hypertension. Direct antiviral agents are highly effective and safe and can now cure > 90% of the patients. Sustained viral response (SVR) after interferon-based regimens has been associated with improvement in liver function, fibrosis and portal hypertension in a significant proportion of patients, although a point of no return seems to exist from which viral elimination is no longer capable of preventing portal hypertension progression and liver decompensation. Indeed, although SVR is associated with improvement of hepatic venous pressure gradients and therefore a decreased risk of de novo esophageal varices, several studies show that viral clearance does not eliminate the risk of variceal progression, liver decompensation and death in patients with pre-established portal hypertension. Although evidence about the effects of direct antiviral agents (DAAs) on clinically significant outcomes is still scarce and with short follow-up, DAAs can decrease the burden of the disease if patients are timely treated before significant fibrosis and portal hypertension develops. Studies with longer follow-up are waited to establish the real magnitude of hepatitis C treatment on portal hypertension. Future studies should also focus on predictors of portal hypertension resolution since it can influence management and avoid unnecessary monitoring