Arrhenius relationship and two-step scheme in AF hyperdynamics simulation of diffusion of Mg/Zn interface

The accelerating factor （AF） method is a simple and appropriate way to investigate the atomic long-time deep diffusion at solid-solid interface. In the framework of AF hyperdynamics （HD） simulation, the relationship between the diffusion coefficient along the direction of z-axis which is normal to the Mg/Zn interface and temperature was investigated, and the AF＇s impact on the diffusion constant （D0） and activation energy （Q^＊） was studied. Then, two steps were taken to simulate the atomic diffusion process and the formation of new phases： one for acceleration and the other for equilibration. The results show that： the Arrhenius equation works well for the description of Dz with different accelerating factors; the AF has no effect on the diffusion constant Do in the case of no phase transition; and the relationship between Q＊ and Q conforms to Q^＊=Q/A. Then, the new Arrhenius equation for AFHD is successfully constructed as Dz=Doexp[-Q/（ART）]. Meanwhile, the authentic equilibrium conformations at any dynamic moment can only be reproduced by the equilibration simulation of the HD-simulated configurations. Key words： accelerating factor method; Arrhenius equation; two-steps scheme; Mg/Zn interface; hyperdynamic simulation

Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis

Portal hypertension is a clinical syndrome which leads to several clinical complications, such as the formation and rupture of esophageal and/or gastric varices, ascites, hepatic encephalopathy and hepato-renal syndrome. In cirrhosis, the primary cause of the increase in portal pressure is the enhanced resistance to portal outflow. However, also an increase in splanchnic blood flow worsens and maintains portal hypertension. The vasodilatation of arterial splanchnic vessels and the opening of collateral circulation are the determinants of the increased splanchnic blood flow. Several vasoactive systems/substances, such as nitric oxide, cyclooxygenase-derivatives, carbon monoxide and endogenous cannabinoids are activated in portal hypertension and are responsible for the marked splanchnic vasodilatation. Moreover, an impaired reactivity to vasoconstrictor systems, such as the sympathetic nervous system, vasopressin, angiotensin II and endothelin-1, plays a role in this process. The opening of collateral circulation occurs through the reperfusion and dilatation of preexisting vessels, but also through the generation of new vessels. Splanchnic vasodilatation leads to the onset of the hyperdynamic circulatory syndrome, a syndrome which occurs in patients with portal hypertension and is characterized by increased cardiac output and heart rate, and decreased systemic vascular resistance with low arterial blood pressure. Understanding the pathophysiology of splanchnic vasodilatation and hyperdynamic circulatory syndrome is mandatory for the prevention and treatment of portal hypertension and its severe complications.

Estrogen improves the hyperdynamic circulation and hyporeactivity of mesenteric arteries by alleviating oxidative stress in partial portal vein ligated rats

AIM:To evaluate the effects of estrogen(E2) on systemic and splanchnic hyperdynamic circulation in portal hypertensive rats.METHODS:Fifty castrated female Sprague-Dawley rats were divided into five groups:sham operation(SO),partial portal vein ligation(PPVL) + placebo(PLAC),PPVL + E2,PPVL + ICI and PPVL + E2 + ICI. Hemodynamic measurements were performed using ultrasonography. Mesenteric arteriole contractility in response to norepinephrine was determined using a vessel perfusion system. Oxidative stress in the mesenteric artery was investigated by in situ detection of the superoxide anion(O2) and hydrogen peroxide(H2O2) concentrations.RESULTS:Treatment with E2 resulted in a significant decrease of portal pressure(P < 0.01) and portal venous inflow(P < 0.05),and higher systemic vascular resistance(P < 0.05) and splanchnic arteriolar resistance(P < 0.01) in PPVL + E2 rats compared to PPVL+ PLAC rats. In the mesenteric arterioles of PPVL +E2 rats,the dose-response curve was shifted left,and the EC50was decreased(P < 0.01). E2 reduced O2 production and H2O2concentration in the mesenteric artery. However,ICI182,780 reversed the beneficial effects of E2,therefore,the systemic and splanchnic hyperdynamic circulation were more deteriorated in ICI182,780-treated rats.CONCLUSION:Treatment with estrogen improved the systemic and splanchnic hyperdynamic circulation in PPVL rats,in part due to the alleviation of oxidative stress.

Role of nitric oxide synthase and cyclooxygenase in hyperdynamic splanchnic circulation of portal hypertension

BACKGROUND: Nitric oxide (NO) and prostacyclin (PGI(2)) are both powerful vasoactive substances correlated with the hyperhemodynamics of portal hypertension (PHT), a common syndrome characterized by a pathological increase in portal venous pressure. The purpose of the present study was to evaluate the possible interaction between these two endothelial vasodilators, together with their respective roles in the hyperdynamic splanchnic circulation of PHT. METHODS: Ninety-six male Sprague-Dawley rats were randomly divided into three groups: intrahepatic portal hypertension (IHPH) induced by injection of CCI4 (n=31), prehepatic portal hypertension (PHPH) induced by partial stenosis of the portal vein (n=33), and sham-operated controls (SO) (n=32). Animals of each group received indomethacin (INDO), a cyclooxygenase (COX) inhibitor, either short-term (7 days) or long-term (15 days), with saline as control. Free portal pressure (FPP), together with the concentration of NO and PGI(2) in serum were measured. The activity of constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) in the abdominal aorta and small intestine were determined by spectrophotometry. RT-PCR was performed to measure the levels of cNOS and iNOS mRNA in the arteries and small intestines. RESULTS: Compared with SO rats, the concentrations of NO and PGI(2) in PHT rats were elevated, which were consistent with the increased FPP (P<0.05). Although administration of INDO persistently decreased the concentration of PGI(2) in serum (P<0.05), the long-term INDO-treated IHPH and PHPH groups had restored splanchnic hyperdynamic circulation, demonstrated by the enhanced FPP (P<0.05). Furthermore, the changes of dynamic circulatory state in both IHPH and PHPH rats were concomitant with the expression and activity of iNOS and the concentration of NO (P<0.05). Although the expression and activity of cNOS in abdominal aorta of PHT rats were higher than in SO rats (P<0.05), there was no difference in small intestinal tissues between PHT and SO rats (P>0.05). Moreover, the changes of iNOS activity and mRNA expression were more marked than cNOS in PHT rats, and there was no difference in expression and activity of cNOS between PHT rats treated by short- and long-term INDO (P>0.05). CONCLUSIONS: iNOS plays an important role in the hemodynamic abnormalities of PHT induced by overproduction of NO. There is a possible interaction between PGI(2) and NO in hyperbemodynamics of PHT, but PGI(2) may not be a mediator in the formation and development of the hyperdynamic circulatory state in PHT rats.

Role of PGI_2 in the formation and maintenance of hyperdynamic circulatory state of portal hypertensive rats

AIM: To investigate the role of prostacyclin (PGI2) and nitric oxide (NO) in the development and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats. METHODS: Ninety male Sprague-Dawley rats were divided into three groups: intrahepatic portal hypertension (IHPH) group by injection of CCI4, prehepatic portal hypertension (PHPH) group by partial stenosis of the portal vein and sham-operation control (SO) group. One week after the models were made, animals in each group were subdivided into 4 groups: saline controlled group (n = 23), Nω-nitro-L-arginine (L-NNA)group (n = 21) group, indomethacin (INDO) group (n = 22) and high-dose heparin group (n = 24). The rats were administrated 1mL of saline, L-NNA (3.3 mg/kg-d) and INDO (5 mg/kg·d) respectively through gastric tubes for one week/then heparin (200 IU/Kg/min) was given to rats by intravenous injection for an hour. Splanchnic and systemic hemodynamics were measured using radioactive microsphere techniques. The serum nitrate/nitrite(NO2-/NO3-) levels as a marker of production of NO were assessed by a colorimetric method, and concentration of 6-keto-PGF1α, a stable hydrolytic product of PGI2, was determined by radioimmunoassay. RESULTS: The concentrations of plasma 6-keto-PGFla (pg/mL) and serum NO2-/NO3- (μmol/L) in IHPH rats (1123.85±153.64, 73.34±4.31) and PHPH rats (891.88±83.11, 75.21±6.89) were significantly higher than those in SO rats (725.53±105.54, 58.79±8.47) (P<0.05). Compared with SO rats, total peripheral vascular resistance (TPR) and spanchnic vascular resistance (SVR) decreased but cardiac index (CI) and portal venous inflow (PVI) increased obviously in IHPH and PHPH rats (P<0.05). L-NNA and indomethacin could decrease the concentrations of plasma 6-keto-PGFla and serum NO2/7NO3-in IHPH and PHPH rats (P<0.05) .Meanwhile, CI, FPP and PVI lowered but MAP, TPR and SVR increased(P<0.05). After deduction of the action of NO, there was no significant correlation between plasma PGI2 level and hemodynamic parameters such as CI, TPR, PVI and SVR. However, after deduction of the action of PGI2, NO still correlated highly with the hemodynamic parameters, indicating that there was a close correlation between NO and the hemodynamic parameters. After administration of high-dose heparin, plasma 6-keto- concentrations in IHPH, PHPH and SO rats were significantly higher than those in rats administrated vehicle (P<0.05). On the contrary, levels of serum NO2-/NO3- in IHPH, PHPH and SO rats were significantly lower than those in rats administrated Vehicle (P<0.05). Compared with those rats administrated vehicle, the hemodynamic parameters of portal hypertensive rats, such as CI and PVI, declined significantly after administration of high-dose heparin (P<0.05), while TPR and SVR increased significantly (P<0.05). CONCLUSION: It is NO rather than PGI2 that is a mediator in the formation and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats.

Cardiac and vascular changes in cirrhosis:Pathogenic mechanisms

Cardiovascular abnormalities accompany both portal hypertension and cirrhosis. These consist of hyperdynamic circulation, defined as reduced mean arterial pressure and systemic vascular resistance, and increased cardiac output. Despite the baseline increased cardiac output, ventricular inotropic and chronotropic responses to stimuli are blunted, a condition known as cirrhotic cardiomyopathy. Both conditions may play an initiating or aggravating pathogenic role in many of the complications of liver failure or portal hypertension including ascites, variceal bleeding, hepatorenal syndrome and increased postoperative mortality after major surgery or liver transplantation. This review briefly examines the major mechanisms that may underlie these cardiovascular abnormalities, concentrating on nitric oxide, endogenous cannabinoids, central neural activation and adrenergic receptor changes. Future work should address the complex interrelationships between these systems.

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.

Cirrhotic cardiomyopathy:A cardiologist's perspective

Cardiac dysfunction is frequently observed in patients with cirrhosis, and has long been linked to the direct toxic effect of alcohol. Cirrhotic cardiomyopathy(CCM) has recently been identified as an entity regardless of the cirrhosis etiology. Increased cardiac output due to hyperdynamic circulation is a pathophysiological hallmark of the disease. The underlying mechanisms involved in pathogenesis of CCM are complex and involve various neurohumoral and cellular pathways, including the impaired β-receptor and calcium signaling, altered cardiomyocyte membrane physiology, elevated sympathetic nervous tone and increased activity of vasodilatory pathways predominantly through the actions of nitric oxide, carbon monoxide and endocannabinoids. The main clinical features of CCM include attenuated systolic contractility in response to physiologic or pharmacologic strain, diastolic dysfunction, electrical conductance abnormalities and chronotropic incompetence. Particularly the diastolic dysfunction with impaired ventricularrelaxation and ventricular filling is a prominent feature of CCM.The underlying mechanism of diastolic dysfunction in cirrhosis is likely due to the increased myocardial wall stiffness caused by myocardial hypertrophy,fibrosis and subendothelial edema,subsequently resulting in high filling pressures of the left ventricle and atrium.Currently,no specific treatment exists for CCM.The liver transplantation is the only established effective therapy for patients with end-stage liver disease and associated cardiac failure.Liver transplantation has been shown to reverse systolic and diastolic dysfunction and the prolonged QT interval after transplantation.Here,we review the pathophysiological basis and clinical features of cirrhotic cardiomyopathy,and discuss currently available limited therapeutic options.

Physiopathology of splanchnic vasodilation in portal hypertension

In liver cirrhosis, the circulatory hemodynamic alterations of portal hypertension signifi cantly contribute to many of the clinical manifestations of the disease. In the physiopathology of this vascular alteration, mesen- teric splanchnic vasodilation plays an essential role by initiating the hemodynamic process. Numerous studies performed in cirrhotic patients and animal models have shown that this splanchnic vasodilation is the result of an important increase in local and systemic vasodilators and the presence of a splanchnic vascular hyporesponsiveness to vasoconstrictors. Among the molecules and factors known to be potentially involved in this arterial vasodilation, nitric oxide seems to have a crucial role in the physiopathology of this vascular alteration. However, none of the wide variety of mediators can be described as solely responsible, since this phenomenon is multifactorial in origin. Moreover, angiogenesis and vascular remodeling processes alsoseem to play a role. Finally, the sympathetic nervous system is thought to be involved in the pathogenesis of the hyperdynamic circulation associated with portal hypertension, although the nature and extent of its role is not completely understood. In this review, we discuss the different mechanisms known to contribute to this complex phenomenon.

Pre-and postoperative systemic hemodynamic evaluation in patients subjected to esophagogastric devascularization plus splenectomy and distal splenorenal shunt:A comparative study in schistomomal portal hypertension

AIM: To investigate the systemic hemodynamic effects of two surgical procedures largely employed for treatment of schistosomal portal hypertension. METHODS: Thirty-six patients undergoing elective surgical treatment of portal hypertension due to hepatosplenic mansonic schistosomiasis were prospectively evaluated. All patients were subjected to preoperative pulmonary artery catheterization; 17 were submitted to esophagogastric devascularization and splenectomy (EGDS) and 19 to distal splenorenal shunt (DSRS). The systemic hemodynamic assessment was repeated 4 d after the surgical procedure. RESULTS: Preoperative evaluation revealed (mean ± SD) an increased cardiac index (4.78 ± 1.13 L/min per m2),associated with a reduction in systemic vascular resistance index (1457 ± 380.7 dynes.s/cm5.m2). The mean pulmonary artery pressure (18 ± 5.1 mmHg) as well as the right atrial pressure (7.9 ± 2.5 mmHg) were increased,while the pulmonary vascular resistance index (133 ± 62 dynes.s/cm5.m2) was decreased. Four days after EGDS,a significant reduction in cardiac index (3.80 ± 0.4 L/min per m2,P < 0.001) and increase in systemic vascular resistance index (1901.4 ± 330.2 dynes.s/cm5. m2,P < 0.001) toward normal levels were observed. There was also a significant reduction in pulmonary artery pressure (12.65 ± 4.7 mmHg,P < 0.001) and no significant changes in the pulmonary vascular resistance index (141.6 ± 102.9 dynes.s/cm5.m2). Four days after DSRS,a non-significant increase in cardiac index (5.2 ± 0.76 L/min per m2) and systemic vascular resistance index (1389 ± 311 dynes.s/cm5.m2) was observed. There was also a non-significant increase in pulmonary artery pressure (19.84 ± 5.2 mmHg),right cardiac work index (1.38 ± 0.4 kg.m/m2) and right ventricular systolic work index (16.3 ± 6.3 g.m/m2),without significant changes in the pulmonary vascular resistance index (139.7 ± 67.8 dynes.s/cm5.m2). CONCLUSION: The hyperdynamic circulatory state observed in mansonic schistosomiasis was corrected by EGDS,but was maintained in patients who underwent DSRS. Similarly,the elevated mean pulmonary artery pressure was corrected after EGDS and maintained after DSRS. EGDS seems to be the most physiologic surgery for patients with schistosomal portal hypertension.

Overproduction of nitric oxide inhibits vascular reactivity in portal hypertensive rats

IM To evaluate the relationship between nitric oxide (NO) and hyperdynamic circulatory status in portal hypertension.METHODS Twenty male SpragueDawley rats (weighing 200g±20g) randomized into two groups, portal hypertension group (n=12) and the controls (n=8). Portal hypertensive models were established by means of graded constriction of the portal vein. The concentrations of nitrite (NO2) in portal vein and peripheral blood were measured to reflect NO levels with flourimetric analysis. The reactivitiy of isolated abdominal aortic rings from partial portal veinconstricted and shamoperated rats was observed by potassium chloride (KCl) (10mmol/L-80mmol/L) and phenylephrine (10-9mol/L10-4mol/L) with or without NO synthase inhibitor NωnitroLarginine (LNNA).RESULTS Serum concentrations of NO2 in portal vein (0766μmol/L±0097μmol/L) and peripheral blood (0687μmol/L±0092μmol/L) were elevated in portal hypertensive rats as compared with those in controls (0613μmol/L±0084μmol/L, 0591μmol/L±0045μmol/L, P<001, respectively). The rates of NO2 in portal vein blood were markedly higher than those in peripheral blood (P<005) of portal hypertensive rats. Abdominal aortic rings from portal veinconstricted rats exhibited significantly impaired contractility to phenylephrine and potassium chloride as compared with the controls. The EC50 values of KCl were markedly higher in portal hypertensive rings (265mmol/L±09mmol/L) than those of the control rings (223mmol/L±17mmol/L, P<001), and so were the EC50 values of phenylephrine (372nmol/L±04nmol/L) vs (281nmol/L±02nmol/L, P<001). After preincubation of rings with LNNA, the difference in EC50 values no longer statistically significant between portal hypertensive and control rings in both KCl (2018mmol/L±08mmol/L, and 194mmol/L±12mmol/L, P>005) and phenylephrine (224nmol/L±18nmol/L, 218nmol/L±14nmol/L, P>005). However, the maximal KCl and phenylephrineinduced contractions were still lower in portal hypertensive rings (KCl: 108g±01g, phenylephrine: 143g±014g) than those of the control rings (KCl: 121g±011g, phenylephrine: 172g±011g, P<005, respectively). This showed that addition of the NO synthase inhibitor LNNA could partially restore contractile responses to KCl and phenylephrine in portal hypertensive rings.CONCLUSION NO overproduction inhibits the vascular reactivity to vasocontrictors, and it might be one of the main causes which results in vasodilatation and hyperdynamic circulatory status in portal hypertension.

Stability of cirrhotic systemic hemodynamics ensures sufficient splanchnic blood flow after living-donor liver transplantation in adult recipients with liver cirrhosis

AIM： To investigate the correlation between systemic hemodynamics and splanchnic circulation in recipients with cirrhosis undergoing living-donor liver transplantation （LDLT）, and to clarify how systemic hemodynamics impact on local graft circulation after LDLT.METHODS： Systemic hemodynamics, indocyanine green （ICG） elimination rate （K,cG） and splanchnic circulation were simultaneously and non-invasively investigated by pulse dye densitometry （PDD） and ultrasound. Accurate estimators of optimal systemic hyperdynamics after LDLT [i.e., balance of cardiac output （CO） to blood volume （BV） and mean transit time （MTT）, defined as the time required for half the administered ICG to pass through an attached PDD sensor in the first circulation] were also measured. Thirty recipients with cirrhosis were divided into two groups based on clinical outcomes corresponding to postoperative graft function.RESULTS： Cirrhotic systemic hyperdynamics characterized by high CO, expanded BV and low total peripheral resistance （TPR） were observed before LDLT. TPR reflecting cirrhotic vascular alterations was slowly restored after LDLT in both groups. Although no significant temporal differences in TPR were detected between the two groups, CO/BV and M＇IT differed significantly. Recipients with good outcomes showed persistent cirrhotic systemic hyperdynamics after LDLT, whereas recipients with poor outcomes presented with unstable cirrhotic systemic hyperdynamics and severely decreased KICG. Systemic hyperdynamic disorders after LDLT impacted on portal venous flow but not hepatic arterial flow.CONCLUSION： We conclude that subtle systemic hyperdynamics disorders impact on splanchnic circulation, and that an imbalance between CO and BV decreases portal venous flow, which results in critical outcomes.

Splenic vasculopathy in portal hypertension patients

AIM： To investigate the interaction between portal hypertension, splanchnic hyperdynamic circulation and splanchnic vasculopathy by observing splenic arterial and venous pathological changes and the role of extracellular matrix in the pathogenesis of portal hypertensive vasculopathy by measuring the expression of type Ⅰ and type Ⅲ procollagen mRNA in splenic venous walls of portal hypertensive patients. METHODS： Morphological changes of splenic arteries and veins taken from portal hypertensive patients （n = 20） and normal controls （n = 10） were observed under optical and electron microscope. Total RNA was extracted and the expression of type Ⅰ and type Ⅲ procollagen mRNA in splenic venous walls of portal hypertensive patients （n= 20） was semi-quantitatively detected using reverse transcription-polymerase chain reaction （RT-PCR）. RESULTS： Under optical microscope, splenic arterial intima was destroyed and internal elastic membrane and medial elastic fibers of the splenic arterial walls were degenerated and broken. Splenic venous intima became remarkably thick. Endothelial cells were not intact with formation of mural thrombus. The tunica media became thickened significantly due to hypertrophy of smooth muscles. Fibers and connective tissues were increased obviously. Under electron microscope, smooth muscle cells of the splenic arteries were degenerated and necrotized. Phenotypes of smooth muscle cells changed from constrictive into synthetic type. Red blood cells and platelets accumulated around the damaged endothelial cells. Synthetic smooth muscle cells were predominant in splenic veins and their cytoplasma had plentiful rough endoplasmic reticulum ribosomes and Golgi bodies. Along the vascular wall, a lot of collagen fibers were deposited, the intima was damaged and blood components accumulated. There was no significant difference in the expression of type Ⅰ procollagen mRNA in splenic venous wall between the patients with portal hypertension and those without portal hypertension （P〉0.05）, but the expression of type Ⅲ procoagen mRNA was significantly stronger in the patients with portal hypertension than in those without portal hypertension （P〈 0.01）. CONCLUSION： Type Ⅲ procollagen and collagen might be important extra-cellular matrix resulting in neointimal formation and vascular remodeling in the pathogenesis of portal hypertensive vasculopathy. The pathological changes in splenic arteries and veins exist in portal hypertension patients. There might be an interaction between portal hypertension, splanchnic hyperdynamic circulation and splanchnic vasculopathy.

Peculiar characteristics of portal-hepatic hemodynamics of alcoholic cirrhosis

Alcohol-related cirrhosis is a consequence of heavy and prolonged drinking. Similarly to patients with cirrhosis of other etiologies, patients with alcoholic cirrhosis develop portal hypertension and the hepatic, splanchnic and systemic hemodynamic alterations that follow. However, in alcoholic cirrhosis, some specific features can be observed. Compared to viral cirrhosis, in alcohol-related cirrhosis sinusoidal pressure is generally higher, hepatic venous pressure gradient reflects portal pressure better, the portal flow perfusing the liver is reduced despite an increase in liver weight, the prevalence of reversal portal blood flow is higher, a patent paraumbilical vein is a more common finding and signs of hyperdynamic circulations, such as an increased cardiac output and decreased systemic vascular resistance, are more pronounced. Moreover, alcohol consumption can acutely increase portal pressure and portal-collateral blood flow. Alcoholic cardiomyopathy, another pathological consequence of prolonged alcohol misuse, may contribute to the hemodynamic changes occurring in alcohol-related cirrhosis. The aim of this review was to assess the portal-hepatic changes thatoccur in alcohol-related cirrhosis, focusing on the differences observed in comparison with patients with viral cirrhosis. The knowledge of the specific characteristics of this pathological condition can be helpful in the management of portal hypertension and its complications in patients with alcohol-related cirrhosis.

Gut-liver axis in cirrhosis:Are hemodynamic changes a missing link?

Recent evidence suggests that the condition of the gut and its microbiota greatly influence the course of liver disease,especially cirrhosis.This introduces the concept of the gut-liver axis,which can be imagined as a chain connected by several links.Gut dysbiosis,small intestinal bacterial overgrowth,and intestinal barrier alteration lead to bacterial translocation,resulting in systemic inflammation.Systemic inflammation further causes vasodilation,arterial hypotension,and hyperdynamic circulation,leading to the aggravation of portal hypertension,which contributes to the development of complications of cirrhosis,resulting in a poorer prognosis.The majority of the data underlying this model were obtained initially from animal experiments,and most of these correlations were further reproduced in studies including patients with cirrhosis.However,despite the published data on the relationship of the disorders of the gut microbiota with the complications of cirrhosis and the proposed pathogenetic role of hemodynamic disorders in their development,the direct relations between gut dysbiosis and hemodynamic changes in this disease are poorly studied.They remain a missing link in the gut-liver axis and a challenge for future research.

Research progress of vasculopathy in portal hypertension

Portal hypertension, one of the vascular diseases, not only has lesions in liver, but also changes in vascular structures and functions of extrahepatic portal system, systemic system and pulmonary drculation. The pabhological changes of vasculopathy in portal hypertension include remodeling of arterialized visceral veins, intimal injury of visceral veins and destruction of contractile structure in visceral arterial wall. The mechanisms of vasculopathy in portal hypertension may be attributed to the changes of hemodynamics in portal system, immune response, gene modulation, vasoactive substances, and intrahepatic blood flow resistance. Portal hypertension can cause visceral hyperdynamic circulation, and the development and progression of visceral vasculopathy, while visceral vasculopathy can promote the development and progression of portal hypertension and visceral hyperdynamic circulation in turn. The aforementioned three factors interact in the pathogenesis of hepatic cirrhosisinduced portal hypertension and are involved in hemorrhage due to varicose vein rupture.

Systemic hemodynamics in advanced cirrhosis: Concerns during perioperative period of liver transplantation

Advanced liver cirrhosis is usually accompanied by portal hypertension. Long-term portal hypertension results in various vascular alterations. The systemic hemodynamic state in patients with cirrhosis is termed a hyperdynamic state. This peculiar hemodynamic state is characterized by an expanded blood volume, high cardiac output, and low total peripheral resistance. Vascular alterations do not disappear even long after liver transplantation(LT), and recipients with cirrhosis exhibit a persistent systemic hyperdynamic state even after LT. Stability of optimal systemic hemodynamics is indispensable for adequate portal venous flow(PVF) and successful LT, and reliable parameters for optimal systemic hemodynamics and adequate PVF are required. Even a subtle disorder in systemic hemodynamics is precisely indicated by the balance between cardiac output and blood volume. The indocyanine green(ICG) kinetics reflect the patient's functional hepatocytes and effective PVF, and PVF is a major determinant of the ICG elimination constant(kICG) in the well-preserved allograft. The kICG value is useful to set the optimal PVF during living-donor LT and to evaluate adequate PVF after LT. Perioperative management has a large influence on the postoperative course and outcome; therefore, key points and unexpected pitfalls for intensive management are herein summarized. Transplant physicians should fully understand the peculiar systemic hemodynamic behavior in LT recipients with cirrhosis and recognize the critical importance of PVF after LT.

Pathological abnormalities in splenic vasculature in non-cirrhotic portal hypertension:Its relevance in the management of portal hypertension

BACKGROUND Portal hypertension(PH)is associated with changes in vascular structure and function of the portosplenomesenteric system(PSMS).This is referred to as portal hypertensive vasculopathy.Pathological abnormalities of PSMS has been described in the literature for cirrhotic patients.Raised portal pressure and hyperdynamic circulation are thought to be the underlying cause of this vasculopathy.In view of this,it is expected that pathological changes in splenic and portal vein similar to those reported in cirrhotic patients with PH may also be present in patients with non-cirrhotic PH(NCPH).AIM To investigate pathological abnormalities of splenic vein in patients with NCPH,and suggest its possible implications in the management of PH.METHODS A prospective observational study was performed on 116 patients with NCPH[Extrahepatic portal vein obstruction(EHPVO):53 and non-cirrhotic portal fibrosis(NCPF):63]who underwent proximal splenorenal shunt(PSRS),interposition shunt or splenectomy with devascularization in JIPMER,Pondicherry,India,a tertiary level referral center,between 2011-2016.All patients were evaluated by Doppler study of PSMS,computed tomography portovenogram and upper gastrointestinal endoscopy.An acoustic resonance forced impulse(ARFI)scan and abdomen ultrasound were done for all cases to exclude cirrhosis.Intraoperative and histopathological assessment of the harvested splenic vein was performed in all.The study group was divided into delayed and early presentation based on the median duration of symptoms(i.e.108 mo).RESULTS The study group comprising of 116 patients[77(66%)females and 39(34%)males]with NCPH had a median age of 22 years.Median duration of symptoms was 108 mo.The most common presentation in both EHPVO and NCPF patients was upper gastrointestinal bleeding(hematemesis and melena).The ARFI scan revealed a median score of 1.2(1.0-1.8)m/s for EHPVO and 1.5(0.9-2.8)m/s for NCPF.PSRS was performed in 84 patients(two of whom underwent interposition PSRS using a 10 mm Dacron graft);splenoadrenal shunt in 9;interposition mesocaval shunt in 5;interposition 1st jejunal to caval shunt in 1 patient and devascularization with splenectomy in 17 patients.Median presplenectomy portal pressure was 25(range:15-51)mm Hg.In 77%cases,the splenic vein was abnormal upon intraoperative assessment.Under macroscopic examination,wall thickening was observed in 108(93%),venous thrombosis in 32(28%)and vein wall calcification in 27(23%)cases.Upon examination under a surgical magnification loupe,21(18%)patients had intimal defects in the splenic vein.Histopathological examination of veins was abnormal in all cases.Medial hypertrophy was noted in nearly all patients(107/116),while intimal fibrosis was seen in 30%.Ninety one percent of patients with intimal fibrosis also had venous thrombosis.Vein wall calcification was found in 22%,all of whom had intimal fibrosis and venous thrombosis.The proportion of patients with pathological abnormalities in the splenic vein were significantly greater in the delayed presentation group as compared to the early presentation group.CONCLUSION Pathological changes in the splenic vein similar to those in cirrhotic patients with PH are noted in NCPH.We recommend that PH in NCPH be treated as systemic and pulmonary hypertension equivalent in the gastrointestinal tract,and that early aggressive therapy be initiated to reduce portal pressure and hemodynamic stress to avoid potential lethal effects.