Insight into congenital absence of the portal vein： Is it rare？

Congenital absence of portal vein （CAPV） was a rare event in the past. However, the number of detected CAPV cases has increased in recent years because of advances in imaging techniques. Patients with CAPV present with portal hypertension （PH） or portosystemic encephalopathy （PSE）, but these conditions rarely occur until the patients grow up or become old. The patients usually visit doctors for the complications of venous shunts, hepatic or cardiac abnormalities detected by ultrasonography （US）, computed tomography （CT） and magnetic resonance imaging （MR1）. The etiology of this disease is not clear, but most investigators consider that it is associated with abnormal embryologic development of the portal vein. Usually, surgical intervention can relieve the symptoms and prevent occurrence of complications in CAPV patients. Moreover, its management should be stressed on a case-by-case basis, depending on the type or anatomy of the disease, as well as the symptoms and clinical conditions of the patient.     

Nitric oxide synthase and heme oxygenase expressions in human liver cirrhosis

AIM:Portal hypertension is a common complication ofliver cirrhosis.Intrahepatic pressure can be elevatedin several ways.Abnormal architecture affectingthe vasculature,an increase in vasoconstrictors andincreased circulation from the splanchnic viscera intothe portal system may all contribute.It follows thatendogenous vasodilators may be able to alleviate thehypertension.We therefore aimed to investigate thelevels of endogenous vasodilators,nitric oxide(NO)andcarbon monoxide(CO)through the expression of nitricoxide synthase(NOS)and heme oxygenase(HO).METHOD:Cirrhotic(n=20)and non-cirrhotic(n=20)livers were obtained from patients whohad undergone surgery.The mRNA and proteinexpressions of the various isoforms of NOS and HOwere examined using competitive PCR,Western Blot andimmunohistochemistry.RESULTS:There was no significant change in eitherinducible NOS(iNOS)or neuronal NOS(nNOS)expressions while endothelial NOS(eNOS)was up-regulated in cirrhotic livers.Concomitantly,caveolin-1,anestablished down-regulator of eNOS,was up-regulated.Inducible HO-1 and constitutive HO-2 were found toshow increased expression in cirrhotic livers albeit indifferent localizations.CONCLUSION:The differences of NOS expressionmight be due to their differing roles in maintaining liverhomeostasis and/or involvement in the pathology ofcirrhosis.Sheer stress within the hypertensive liver mayinduce increased expression of eNOS.In turn,caveolin-1 is also increased.Whether this serves as a defensemechanism against further cirrhosis or is a consequenceof cirrhosis,is yet unknown.The elevated expressionof HO-1 and HO-2 suggest that CO may compensatein its role as a vasodilator albeit weakly.It is possiblethat CO and NO have parallel or coordinated functionswithin the liver and may work antagonistically in thepathophysiology of portal hypertension.     

Ultrasonic diagnosis of patients with clonorchiasis and preliminary study of pathogenic mechanism

Objective:To discuss the liver function damage mechanism of patients with clonorchiasis by analyzing the ultrasound characteristics,liver function,change of the serum inflammatory factors and cell apoptosis factors.Methods:Color Doppler ultrasound technique was adopted to detect the portal vein and blood flow change of patients with clonorchiasis;ELISA was used to determine the level of different serum inflammatory factors.The levels of serum total bilirubin,serum albumin and glutamic-pyruvic transaminase were detected by automatic biochemical analyzer.Western blot was used to determine the expression of proteins relevant to apoptosis.Results:Compared with the health control group,the trunk diameter of portal vein and the thickness of spleen,as well as the hepatic artery pulsation index of clonorchiasis patients increased obviously,the mean blood flow velocity of portal vein(P0.05 or P0.01) decreased.The content of total bilirubin and transaminase in plasma increased significantly,but albumin decreased(P0.05).Levels of TNF-α,IL-6 and IFN-γ increased remarkably,and the level of every factor was significantly different among patients with Child-Pugh Ⅰ,Child-Pugh Ⅱ and Child-Pugh Ⅲ classification of liver function(P0.05 or P0.01).With the exacerbation of liver dysfunction,levels of TNF-α,IL-6 and IFN-γ gradually increased(P0.05).Compared with the healthy control group,the expression quantity of apoptosis protein Fas,FasL,Bax and Caspase-3 increased significantly(P0.05 or P0.01),but Bcl-2 decreased(P0.05).Conclusions:Changes of ultrasonic characteristics and liver dysfunction,caused by liver fluke infection,may be related to that both inflammatory response and apoptosis response have participated in the pathogenic process and liver damage course of clonorchiasis.     

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.     

Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia

A "leaky gut" may be the cutting edge for the passage of toxins, antigens or bacteria into the body, and may play a pathogenic role in advanced liver cirrhosis and its complications. Plasma endotoxin levels have been admitted as a surrogate marker of bacterial translocation and close relations of endotoxemia to hyperdynamic circulation, portal hypertension, renal, cardiac, pulmonary and coagulation disturbances have been reported. Bacterial overgrowth, increased intestinal permeability, failure to inactivate endotoxin,activated innate immunity are all likely to play a role in the pathological states of bacterial translocation. Therapeutic approach by management of the gut-liver axis by antibiotics, probiotics, synbiotics, prebiotics and their combinations may improve the clinical course of cirrhotic patients. Special concern should be paid on anti-endotoxin treatment. Adequate management of the gut-liver axis may be effective for prevention of liver cirrhosis itself by inhibiting the progression of fibrosis.     

Is portal vein cavernous transformation a component of congenital hepatic fibrosis？

Congenital hepatic fibrosis （CHF） is an autosomal recessive disorder that belongs to the family of fibropolycystic liver diseases. This family includes a spectrum of disorders which are usually found in combination with each other and are usually inherited. Clinically fibropolycystic diseases have three effects being present in different proportions, those of a space occupying lesion, of portal hypertension and of cholangitis. In most patients, the first manifestations of CHF are signs and symptoms related to portal hypertension such as splenomegaly and varices. Portal hypertension in these patients has been attributed to the hypoplasia or compression of the portal vein radicles in the fibrous bands. Cavernous transformation of the portal vein （CTPV） is a relatively rare condition resulting from extrahepatic portal vein obstruction with recanalization or collateral vein formation to bypass the obstruction. It has been found that patients with CHF having an accompanying CTPV have relatively large splenomegaly and suffers more frequent episodes of bleeding from esophageal varices.We believe that CTPV is a congenital component of CHF and also one of the important causative factors of portal hypertension in these patients.     

Current concepts on the role of nitric oxide in portal hypertension

Portal hypertension(PHT) is defined as a pathological increase in portal venous pressure and frequently accompanies cirrhosis.Portal pressure can be increased by a rise in portal blood flow,an increase in vascular resistance,or the combination.In cirrhosis,the primary factor leading to PHT is an increase in intra-hepatic resistance to blood flow.Although much of this increase is a mechanical consequence of architectural disturbances,there is a dynamic and reversible component that represents up to a third of the increased vascular resistance in cirrhosis.Many vasoactive substances contribute to the development of PHT.Among these,nitric oxide(NO) is the key mediator that paradoxically regulates the sinusoidal(intra-hepatic) and systemic/splanchnic circulations.NO deficiency in the liver leads to increased intra-hepatic resistance while increased NO in the circulation contributes to the hyperdynamic systemic/splanchnic circulation.NO mediated-angiogenesis also plays a role in splanchnic vasodilation and collateral circulation formation.NO donors reduce PHT in animals models but the key clinical challenge is the development of an NO donor or drug delivery system that selectively targets the liver.     

Deep vein thrombosis and pulmonary embolism in cirrhotic patients:Systematic review

Patients with liver cirrhosis were traditionally believed to be protected against development of blood clots.Lately,studies have shown that these patients may probably be at an increased risk of venous thrombotic complications.Although the hemostatic changes in the chronic liver disease patients and the factors that may predict bleeding vs thrombotic complications remains an area of active research,it is believed that the coagulation cascade is delicately balanced in these patients because of parallel reduced hepatic synthesis of pro and anticoagulant factors.Thrombotic state in cirrhotic patients is responsible for not only portal or non-portal thrombosis[deep vein thrombosis(DVT)and pulmonary embolism(PE)];it has also been associated with progression of liver fibrosis.The use of anticoagulants in cirrhosis patients is a challenging,and often a scary situation.This review summarizes the current literature on the prevalence of venous thrombosis(DVT and PE),risk factors and safety of prophylactic and therapeutic anticoagulation in patients with chronic liver disease.     

Etiopathogenesis of primary sclerosing cholangitis

Primary sclerosing cholangitis（PSC） is a chronic cholestatic liver disease of unknown etiology but lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for this disease.Associations with inflammatory bowel disease（IBD） especially ulcerative colitis（UC）,and with particular autoimmune diseases,as well as the genetic associations further suggest PSC may be an immune-mediated disease.The immunogenetics of PSC have been the subject of active research and several HLA and non-HLA associated genes have been implicated in the development of the disease.Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease.PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and hence evoking an abnormal immune response.     

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,angiotensinⅡand 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 pa-tients 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.     

Direct measurement of hepatic blood flow in native and transplanted organs, with accompanying systemic hemodynamics.

The purpose of this study was to investigate intraoperatively a population of patients with end-stage liver disease before and after liver transplantation with respect to (a) the range of hepatic and systemic hemodynamics and their changes associated with transplantation and (b) the ability to identify native hemodynamic correlates with specific diagnostic groups. Hepatic artery and portal vein blood flows were determined with square-wave electromagnetic flowmetry. Significant differences related to the type of preservation solution used--Euro-Collins or University of Wisconsin--were identified in some hepatic and systemic hemodynamic measurements from the graft livers. Specifically, cardiac output, total liver blood flow and liver weight were significantly increased in the Euro-Collins group compared with the native and University of Wisconsin groups. Hepatic artery flow was significantly greater and portal vein pressure was significantly lower in the University of Wisconsin group than in the native or Euro-Collins group. In general, comparing the graft and native livers, hepatic artery and portal vein blood flow increased significantly after transplantation, as did hepatic oxygen consumption. Portal vein pressures were dramatically reduced, but systemic arterial pressure remained remarkably constant. The percentage of cardiac output going to the liver increased, as did the portal vein percentage of the total liver blood flow. Diagnostic groups could not clearly be associated with characteristic native liver or systemic hemodynamics. Hemodynamics may be associated more with the stage of the disease process than the disease itself.     

Hemodynamics during liver transplantation: the interactions between cardiac output and portal venous and hepatic arterial flows.

Liver blood flow and systemic hemodynamics were measured intraoperatively in 34 patients after liver transplantation. Ultrasound transit-time flow probes measured hepatic arterial and portal venous flow over 10 to 75 min 1 to 3 hr after reperfusion. Cardiac output was measured by thermodilution. Mean cardiac output was 9.5 +/- 2.8 L/min; the mean total liver blood flow of 2,091 +/- 932 ml/min was 23% +/- 11% of cardiac output. Mean portal flow of 1,808 +/- 929 ml/min was disproportionately high at 85% +/- 10% of total liver blood flow. Correlation analysis showed a significant (p less than 0.01; r = 0.42) correlation between cardiac output and portal venous flow and a trend toward negative correlation (p = 0.087) between cardiac output and hepatic arterial flow. These data show that increased flow in the newly transplanted liver is predominantly portal venous flow and is associated with high cardiac output and reduced hepatic arterial flow. In the last 13 patients studied, portal flow was reduced by 50% and the hepatic artery response was measured. We saw a significant (p less than 0.05) increase in hepatic artery flow from 322 +/- 228 to 419 +/- 271 ml/min, indicating an intact hepatic arterial buffer response. The hepatic artery response also showed that it is a reversible rather than a fixed resistance that contributes to the low hepatic artery flow in these patients.     

Drug therapy for portal hypertension

Drugs used to treat portal hypertension cause constriction of mesenteric arterioles, reducing inflow to the portal venous system, portal pressure, and flow through portasystemic collaterals (such as esophageal varices). Vasopressin and somatostatin are direct vasoconstrictors. Propranolol acts by blocking vasodilatory beta 1 receptors and reducing cardiac output. A major side effect of vasopressin therapy is impaired cardiac performance secondary to coronary vasoconstriction and increased work against high arterial pressure. Infusion of vasopressin together with a cardiac inotrope or a vasodilator, and administration of vasopressin as an inactive "hormonogen" which is slowly released in vivo, may lessen adverse effects. Somatostatin appears to act selectively in the mesenteric circulation. Controlled trials indicate that vasopressin may be useful for controlling hemorrhage from esophageal varices and that somatostatin works at least as well as vasopressin. Propranolol treatment has been used to prevent variceal bleeding; however, controlled trials of its effectiveness have produced conflicting results.     

Effects of prostaglandin inhibition on systemic and hepatic hemodynamics in patients with cirrhosis of the liver

The role of prostaglandins in the pathogenesis of the circulatory abnormalities of cirrhosis was investigated by studying the effects of prostaglandin inhibition with indomethacin (50 mg/8 h for 24 h) on the systemic and splanchnic hemodynamics in 13 patients with cirrhosis of the liver. Indomethacin administration significantly reduced cardiac output (from 7.44 +/- 0.7 to 6.78 +/- 0.7 L/min, p less than 0.05) and increased peripheral vascular resistance (from 990 +/- 104 to 1155 +/- 140 dyn X s X cm-5, p less than 0.05). Arterial pressure was not modified. These changes in systemic hemodynamics were associated with a significant reduction in hepatic blood flow (from 1.88 +/- 0.43 to 1.48 +/- 0.3 L/min, p less than 0.05) and with a slight decrease of portal pressure (from 18.8 +/- 1.3 to 17.5 +/- 1.4 mmHg, p less than 0.05). These results suggest that endogenous prostaglandins contribute to the increased cardiac output and diminished vascular resistance observed in cirrhosis of the liver. In addition, by promoting splanchnic vasodilation, prostaglandins may contribute to increased portal pressure in these patients.     

Selective and non-selective beta receptor blockade in the reduction of portal pressure in patients with cirrhosis and portal hypertension.

To elucidate the mechanisms by which beta receptor blockade leads to a reduction of portal pressure, 18 patients with cirrhosis and portal hypertension were given comparable doses of propranolol or metoprolol. The fall in portal pressure was more marked with propranolol together with a significant reduction in hepatic blood flow, which was not seen with metoprolol. No correlation between the reduction in cardiac output and the decrease in portal pressure or changes in hepatic blood flow could be elicited in each group, but there was a direct relationship between the decrease in hepatic blood flow and fall in portal pressure in the propranolol treated patients. The difference observed may be related to blockade of beta 2 vasodilator receptors in the splanchnic circulation which will occur only with propranolol and lead to a greater fall in splanchnic blood flow than will be produced by a reduction in cardiac output alone. Metoprolol, by maintaining effective hepatic blood flow, may be preferable to propranolol in patients with severely impaired liver function.     

Regulatory processes interacting to maintain hepatic blood flow constancy: Vascular compliance, hepatic arterial buffer response, hepatorenal reflex, liver regeneration, escape from vasoconstriction

Constancy of hepatic blood flow (HBF) is crucial for several homeostatic roles. The present conceptual review focuses on interrelated mechanisms that act to maintain a constant HBF per liver mass. The liver cannot directly control portal blood flow (PF); therefore, these mechanisms largely operate to compensate for PF changes. A reduction in PF leads to reduced intrahepatic distending pressure, resulting in the highly compliant hepatic vasculature passively expelling up to 50% of its blood volume, thus adding to venous return, cardiac output and HBF. Also activated immediately upon reduction of PF are the hepatic arterial buffer response and an HBF-dependent hepatorenal reflex. Adenosine is secreted at a constant rate into the small fluid space of Mall which surrounds the terminal branches of the hepatic arterioles, portal venules and sensory nerves. The concentration of adenosine is regulated by washout into the portal venules. Reduced PFreduces the washout and the accumulated adenosine causes dilation of the hepatic artery, thus buffering the PF change. Adenosine also activates hepatic sensory nerves to cause reflex renal fluid retention, thus increasing circulating blood volume and maintaining cardiac output and PF. If these mechanisms are not able to maintain total HBF, the hemodynamic imbalance results in hepatocyte proliferation, or apoptosis, by a shear stress/nitric oxide-dependent mechanism, to adjust total liver mass to match the blood supply. These mechanisms are specific to this unique vascular bed and provide an excellent example of multiple integrative regulation of a major homeostatic organ.     

Transjugular intrahepatic portosystemic shunt prior to cardiac surgery with cardiopulmonary bypass in patients with cirrhosis and portal hypertension

Because of the increased complications associated with cardiac surgery in patients with cirrhosis and portal hypertension, various preoperative preparations have been utilised. In order to reduce the bleeding risk by decompressing portosystemic collaterals and to correct the fluid shift, we performed transjugular intrahepatic portosystemic shunt (TIPS) in two patients with cirrhosis and portal hypertension prior to major cardiac surgery with cardiopulmonary bypass. Both patients had satisfactory surgical outcome with no bleeding complications. One patient developed hepatic encephalopathy which was managed medically. We believe that preoperative TIPS benefits the patient with cirrhosis and portal hypertension undergoing cardiac surgery by decreasing the major surgical complications through improvement of fluid imbalance and reduction of the bleeding risk. Because of the risks of TIPS, such as encephalopathy and liver failure, preoperative TIPS placement must be reserved for patients with fluid shift or high risk criteria of bleeding.     

Influence of ascites on splanchnic and systemic hemodynamics in patients with alcoholic cirrhosis

The effect of ascites on splanchnic and systemic hemodynamics was retrospectively studied in 256 patients with alcoholic cirrhosis. The patients were divided into 3 classes: no ascites, moderate ascites, and large ascites. They were also classed into 3 groups according to a modified Pugh classification (ascites was not taken into account). In patients without ascites, cardiac output was positively related to the severity of liver disease. This result was not found in patients with large ascites. Similarly, in patients with no or moderate ascites, the degree of portal hypertension estimated by the hepatic venous pressure gradient was associated with liver failure. In patients with large ascites, hepatic venous pressure gradient was higher than in patients without ascites but this relation was observed only in patients without liver failure. These results show that ascites reduces the relation between cardiac output and liver failure and increases the degree of portal hypertension but not cardiac output.     

Alterations in Splanchnic Blood Flow After Low and High Doses of Ethanol

The purpose of this investigation was to determine the effect of various acute doses of ethanol (1.0, 3.0, 4.0 g/kg) on the distribution of cardiac output (%CO) and blood flow to the splanchnic vascular bed in conscious male Wistar rats. Regional blood flow and cardiac output (CO) were measured by the reference microsphere technique. Mean arterial pressure and CO were significantly reduced 60 min after 3.0 g/kg and 4.0 g/kg of ethanol, while no changes occurred over time in total peripheral vascular resistance or heart rate. Acute ethanol administration produced an early non-sustained increase in portal vein blood flow, that was most pronounced after a low dose of ethanol, and was attenuated after the 3.0 g/kg and 4.0 g/kg doses of ethanol. The early increase in portal vein blood flow produced a corresponding increase in total liver blood flow. Additionally, we found increases in hepatic arterial blood flow after the higher doses. The combined increase in portal vein and hepatic arterial supply to the liver may serve to increase oxygen delivery, more than the singular increase in portal vein blood flow. This early increase in total liver blood flow after high doses of ethanol may be important for protecting hepatocyte function in the presence of high blood ethanol levels.