Nanoselenium and Nanoalginate Modulate Hepatic Structure and Function of Fipronil Treated Rats

Hepatic hemodynamics and cell functions in human and experimental sepsis.

The liver plays a major role in modulating the systemic response in severe sepsis because it contains most of the macrophages of the body (Kupffer cells) able to clear the endotoxin and bacteria that may stimulate the systemic inflammatory response [1-3]. Hepatocytes synthesize the acute phase proteins and the enzymes required to modulate the inflammatory response [4-5]. Additionally, during bacterial translocation from the gut, the liver limits the access of proinflammatory substances into the systemic circulation [6]. Modifications of hepatic blood flow have been extensively studied in experimental sepsis, but these findings are difficult to extrapolate to humans. In human sepsis, hepatic dysfunction is usually mild and is defined by modifications of biochemical tests. However, there is no consensus on the most appropriate criteria to define and quantify hepatic dysfunction, and these criteria do not reflect the full spectrum of alterations in hepatic cell functions encountered in experimental sepsis. Although several articles have reviewed the numerous alterations of hepatic cell functions encountered in these experimental models, none has addressed the modifications of hepatic blood flow and hepatic function observed in humans sepsis. We review these alterations as reported in both clinical and experimental studies. Although all published clinical studies are included in the text, because of the large number of experimental studies, only the most illustrative experimental data are discussed. We hope that this text will contribute to a better understanding of the role of the liver in human sepsis. Modifications of Hepatic Hemodynamics in Sepsis Hepatic Vessels and Cells The liver has a dual blood supply. Approximately two thirds of the blood perfusing the liver is venous and is supplied by the portal vein draining the splanchnic vascular bed, which collects the blood coming from the digestive tract below the diaphragm, the spleen, and the pancreas. One third of the blood perfusing the liver is arterial and is provided through the hepatic artery. Within the liver, the portal vein and the hepatic artery branch in parallel. After a number of divisions, terminal branches of these vessels supply blood to the hepatic capillaries or sinusoids, which are organized in a dense network. In sinusoids, several types of cells have been identified: endothelial cells, Kupffer cells, and stellate cells. Endothelial cells are perforated by large fenestrae and are not surrounded by a basal lamina. Thus, the porosity of the sinusoids enable the dispersion of plasma into the space of Disse (which separates sinusoids and hepatocytes). Endothelial cells have a high endocytic activity and produce various mediators, such as thromboxane and prostaglandins. Stellate cells store intracytoplasmic fat droplets containing vitamin A and synthesize collagen and other constituents of the extracellular matrix. After acute or chronic hepatic injury, stellate cells undergo activation, a process characterized by the conversion to a myofibroblastic phenotype with de novo expression of the cytoskeletal protein smooth muscle alpha-actin. Thus, during sepsis, stellate cells undergo contractile properties and, similar to endothelial cells, participate to the modifications of hepatic blood flow. Kupffer cells are hepatic macrophages and represent 80%-90% of all resident macrophages of the body. They play a major role in the uptake and destruction of bacteria and endotoxin. After activation by endotoxin, they secrete cytokines, lipid mediators such as leukotrienesand prostaglandins, O2-derived radicals, and lysosomal enzymes. Hepatocytes, which represents 60% of hepatic cells, have numerous metabolic functions, including gluconeogenesis and glycogenolysis, protein synthesis (albumin, fibrinogen), urea synthesis, bile formation, and drug biotransformation by cytochrome P-450 enzymes. Estimation of Hepatic Blood Flow in Human Studies Hepatic blood flow in humans has been assessed in septic patients or healthy volunteers injected with endotoxin by clearance methods using indicators injected into the blood and cleared by the liver. The disappearance rate of these indicators is usually used to estimate hepatic blood flow. These methods require the insertion of a catheter into the right hepatic vein under fluoroscopic visualization. Indocyanine green (ICG) is the most commonly used indicator and is injected as a single bolus or infused over a longer period. The continuous ICG infusion method was first described by Bradley et al. [7] and is based on the Fick principle. Under conditions of constant flow, the volume of blood moving through an organ per time (Q) can be calculated by determining the amount of ICG extracted (R) over that time and the difference between ICG concentrations entering (Ci) and leaving (C0) the organ [8]. The Equation forthis relationship is Q = R/(Ci - C0). Under steady-state conditions, the IV infusion rate (I) of ICG removed exclusively by the liver equals the rate of hepatic removal (R = I). Ci is determined from blood collected from a peripheral vein or artery (because the ICG concentrations are similar), and C0 is measured from blood collected in the hepatic vein. Because ICG is distributed only in the plasma, the calculated plasma flow must be converted to blood flow by knowing the hematocrit (Hct): Q (blood flow) = Q (plasma flow) x 1/(1 - Hct). ICG is the preferred dye indicator because it typically has a high hepatic extraction ratio, no extrahepatic uptake, and low toxicity, and it is easily measured by spectrophotometry. The procedure requires that the catheter be positioned correctly in the hepatic vein, deep enough but not wedged. Otherwise, blood from the inferior vena cava can backflow during sampling; such dilution of the hepatic venous sample introduces error. During experimental endotoxemia, a back-diffusion of ICG from hepatocytes into the hepatic vein has also been described [9]. Although the hepatic extraction ratio (ER) estimated by (Ci - C0)/Ci is usually >90% in control patients [8], it is as low as 30% in septic patients [10]. Low extraction and back-diffusion narrow the difference between ICG concentrations in arterial and hepatic vein samples, leading to an overestimation of hepatic blood flow. Moreover, although extrahepatic ICG extraction is small in normal conditions, it is not known whether it is modified in sepsis. Clearance of a single bolus of ICG is also used, allowing repeated tests. Hepatic blood flow obtained by using this technique correlates well with values obtained with the continuous-injection ICG method in patients with liver disease [11]. Estimation of Hepatic Blood Flow in Human Septic Shock Several studies have attempted to determine the consequences of sepsis on hepatosplanchnic blood flow. In volunteers injected with endotoxin (20 U/kg over 5 min), hepatosplanchnic blood flow increases within 1 h, peaks by 3 h, and finally returns to baseline by 6 h [12]. In intensive care units, septic patients are usually ventilated mechanically. To prevent feeding from modifying hepatic blood flow, enteral feeding is withdrawn and septic patients are infused with various electrolyte solutions. These patients have various sources of infection, including intraperitoneal infections. Ruokonen et al. [13] found that hepatosplanchnic blood flow is higher in hyperdynamic septic patients than in patients after uncomplicated cardiac surgery. Because the cardiac index is also higher in these patients, the ratio between hepatosplanchnic blood flow and cardiac output remains constant (approximately 25%). Dahn et al. [14] compared the hepatosplanchnic blood flow in critically ill patients with or without sepsis and found similar results. These studies suggest that hepatosplanchnic blood flow increases proportionately to the cardiac index in patients with sepsis and that the fractional hepatosplanchnic blood flow remains constant. Whether the relationship between hepatosplanchnic blood flow and cardiac output remains constant throughout the evolution of the disease remains to be determined. O2 Delivery and O2 Consumption in the Hepatosplanchnic Region Hepatosplanchnic O2 delivery (Do2) and O2 consumption (Vo2) were also measured in clinical studies. However, the contribution of the liver to the whole hepatosplanchnic Vo2 is impossible to determine because no sample can be collected from the portal vein [15]. Hepatosplanchnic Vo2 is significantly higher in septic patients (1.9 +/- 0.5 mL [middle dot] min-1 [middle dot] kg-1) than in nonseptic patients (1.3 +/- 0.4 mL [middle dot] min-1 [middle dot] kg-1), whereas systemic Vo2 is similar in both groups [14]. Both hepatosplanchnic Vo2 and systemic Vo2 are significantly increased in septic patients and postoperative patients [13]. In healthy volunteers, hepatosplanchnic Vo2 is 66 +/- 5 mL/min before endotoxin administration and increases 120 min (100 +/- 13 mL/min) and 240 min (90 +/- 12 mL/min) after endotoxin administration. Hepatosplanchnic Vo2 returns to baseline by 360 min [12]. Moreover, Do2 is higher in septic shock patients treated with norepinephrine than in patients with severe sepsis who do not receive noradrenaline [16]. This finding contrasts with the common knowledge that norepinephrine infusion decreases hepatosplanchnic blood flow [15]. It is likely that the vascular hyporesponsiveness to norepinephrine observed in the mesenteric circulation during experimental sepsis is an explanation for this finding [17]. Thus, hepatosplanchnic Vo2 is increased during sepsis, but the contribution of the liver to the hepatosplanchnic Vo2 remains unknown. Hepatic Do2 and Vo2 have been measured in large animals. In anesthetized pigs continuously infused with endotoxin, hepatic Do2 and Vo2 did not change over a 24-h experimental period [18]. In a similar experimental model, hepatic Vo2 was maintained over 6 h, whereas Do2 decreased [19]. However, these experimental findings cannot be extrapolated to clinical studies. In septic patients, most of the increased hepatosplanchnic Vo2 is attributed to an increased hepatic glucose production resulting from increased substrate delivery [12,20]. Hepatic amino acid uptake [20] and other hepatic pathways, such as tumor necrosis factor-alpha (TNF-alpha) and free fatty acid production, are also increased in volunteers injected with endotoxin [12]. Relationship Between Vo2 and Do2 in the Hepatosplanchnic Region In critically ill patients, the relationship between Vo2 and Do (2) is used to assess the O2 deficiency leading to organ dysfunction [21]. Over a wide range of Do2 values, Vo2 remains constant as Do2 varies. Organs extract only as much O2 from the blood as needed to maintain cellular metabolism, and Vo2 and Do2 are independent. However, when Do2 decreases below a critical threshold value, Vo2 decreases in direct proportion to Do2, and Vo2 becomes dependent on Do2. This Vo2/Do2 dependency may be responsible for organ dysfunction. To determine whether the increased hepatosplanchnic Vo2 is limited by the regional Do2 in septic patients, both hepatosplanchnic Vo2 and Do2 were measured before and after therapeutic interventions, such as the infusion of packed red blood cells [22] or dobutamine infusion [10,23][13], to study the evolution of the hepatosplanchnic Vo2 while increasing the regional Do2. Ruokonen et al. [13] first reported an increase in hepatosplanchnic Vo2 after the administration of dopamine, dobutamine, or norepinephrine. After the infusion of 2 U of packed red blood cells, the hepatosplanchnic Vo2 moderately increased by 9%, whereas hepatosplanchnic Do2 increased by 26% [22]. These two studies demonstrate a flow-dependent O2 consumption in hepatosplanchnic organs. In contrast, when hepatosplanchnic Vo2 and Do2 were measured before and after the infusion of dobutamine, hepatosplanchnic Vo2 remained constant, whereas hepatosplanchnic Do2 increased by 29% [10]. These contradictory results may be explained by a recent study [23] showing that, in septic patients with a gradient between mixed venous and hepatic vein saturation >10%, both hepatosplanchnic Do2 and Vo2 increased during dobutamine perfusion, demonstrating Vo2/Do2 dependency. In contrast, in patients with a gradient <10%, hepatosplanchnic Vo2 remained constant and the regional Do2 increased with the dobutamine perfusion [23]. Consequently, hepatosplanchnic Do2 seems sufficient to fulfill the regional O2 demand in most septic patients, but not in those with a high gradient between mixed venous and hepatic vein saturation. Lactate Flux in the Hepatosplanchnic Region The evolution of hepatosplanchnic lactate flux has also been determined while the regional Do2 is increased. In a study by Steffes et al. [22], regional lactate uptake did not change in response to the increased hepatosplanchnic Do2. In contrast, lactate uptake increased by 38% in septic patients infused with dobutamine, and the increased lactate uptake was similar for patients who had a Vo2/Do2 dependency and for those in whom Vo2 did not increase in response to the dobutamine perfusion [23]. However, interpreting the evolution of lactate flux while hepatosplanchnic Do2 increases is difficult. During Vo2/Do2 dependency, an increase in Vo2 after Do2 increase is not always associated with an increased lactate uptake because lactate uptake is influenced not only by the amount of O2 available for the conversion of lactate to pyruvate, but also by the total amount of lactate delivered to the liver. Consequently, lactate uptake can increase when blood flow is increased, even in the absence of hypoxia. Moreover, hepatosplanchnic lactate uptake represents the net lactate flux through both the gut and the liver. Because lactate is produced by the gut and taken up by the liver, and because lactate concentrations in portal vein are not available in clinical studies, it is difficult to interpret hepatosplanchnic lactate flux in humans. In summary, sepsis increases hepatosplanchnic blood flow and Vo2. Besides an increased production of TNF-alpha and free fatty acids, hepatic glucose production is likely responsible for the increased hepatosplanchnic Vo2. The increased hepatosplanchnic blood flow, however, may not be sufficient to meet the hepatosplanchnic Vo2 in patients with a high gradient between mixed venous and hepatic vein O2 saturation. Hepatic Blood Flow in Experimental Studies In contrast to human studies, both hepatic artery and portal vein blood flows can be measured in animals. Various models of septic shock have been described, including the injection of endotoxin or bacteria (IV or intraperitoneal injection or perfusion) and cecal ligation and puncture (CLP). These experimental models of sepsis induce either a hypodynamic syndrome (defined mainly by a low cardiac output) or a hyperdynamic syndrome (associated with an increased cardiac output). The type of animals used (for example, pigs do not often develop hyperdynamic syndrome), the treatment (fluid challenge), and the model of sepsis determine whether the syndrome will be hypodynamic or hyperdynamic [24-26]. In septic models associated with hypotension and low cardiac output, hepatic perfusion is compromised by a decrease in both portal vein and hepatic artery flows [27-28]. In rabbits anesthetized with pentobarbital after endotoxin injection, portal vein blood flow decreased, whereas hepatic artery blood flow increased [29]. However, the type of shock induced in these experimental models differs from the classically described hyperdynamic shock observed in humans. In experimental models in which the increased cardiac output is similar to that observed in patients, both hepatic flows increased by 24 h [30]. Moreover, the two hepatic flows also interact to maintain a constant blood flow to the liver. The "hepatic arterial buffer response" [31] is defined as the inverse changes in hepatic artery blood flow in response to the changes in portal flow. For example, an increase in hepatic artery flow compensates for a decrease in portal vein flow, maintaining a constant blood flow to the liver. This hepatic arterial buffer response is preserved in hemorrhagic shock [32] but is altered during sepsis [33]. During endotoxemia, a decrease of portal blood flow is not buffered by an increased of hepatic artery blood flow, and the increased NO production observed in this model is not the cause for the loss of the hepatic arterial buffer response [33]. The isolated perfused liver is also an interesting model for studying the direct effects of endotoxin administration without the interference of cardiac output and other organs. After endotoxin administration, intrahepatic resistances increase. The effect is similar when endotoxin is injected through either the portal vein or the hepatic artery [34]. Thus, both hepatic blood flows increase in experimental septic shock associated with a high cardiac output, but the regulation between the two hepatic flows is altered. Hepatic Cell Functions in Sepsis Hepatic Injury in Clinical Studies Hepatic injury has been investigated mainly in critically ill patients, but few studies have included only septic patients. Criteria used to define hepatic injury are jaundice; hyperbilirubinemia; increase of plasma concentrations of transaminases, alkaline phosphatase, or lactate dehydrogenase; and decrease of serum albumin concentration. These criteria vary among studies (Table 1). A disproportionate increase in plasma concentration of total bilirubin, compared with that in alanine transaminase and aspartate transaminase, is found in septic patients [35]. Prothrombin time has been proposed by Le Gall et al. [36] and Smail et al. [37] as an early criterion of hepatic injury. They suggest that prothrombin time may be abnormal even when the plasma concentration of bilirubin remains within normal limits. To quantify the degree of hepatic injury, scores with a severity grading have also been proposed (Table 2). These scores measure the worst values observed during the disease. An important limitation is that they do not take into consideration the duration of hepatic injury. These scores are similar to those measured in chronic hepatic diseases. Besides the systemic release of various substances by hepatic cells, hepatic injury may also be assessed by the inability of hepatic cells to metabolize exogenous compounds. Maynard et al. [38] used the monethylglycinexylidide formation test to assess hepatic function in critically ill septic patients. After a subtherapeutic injection of lidocaine (1 mg/kg), monethylglycinexylidide (an hepatic metabolite of lidocaine) was measured over the first 3 days after admission. The authors found that the arterial concentration of monethylglycinexylidide was higher in patients who survived than in patients who died. Thus, this test could be an interesting method to assess hepatic dysfunction in critically ill septic patients.Table 1: Criteria for hepatic dysfunction in multiple organ dysfunction syndromeTable 2: Criteria for Hepatic Dysfunction in Multiple Organ Dysfunction Syndrome: Severity Grading ScoreThe occurrence of hepatic injury varies markedly among studies. One reason might be that low-grade hyperbilirubinemia and increased hepatic enzyme go unnoticed in many patients without clinical jaundice. When defined by low-grade hyperbilirubinemia and mild hepatic enzyme increase, hepatic injury is as common as pulmonary and renal failure [39]. Hepatic dysfunction is usually mild during septic shock (Table 1 and Table 2). It can occur 5.7 +/- 7.6 days after surgery [39], after pulmonary failure but before cardiovascular failure [35]. In septic patients without preexisting hepatic disease, the plasma bilirubin concentration may become abnormally increased >1 wk after the initial injury [35]. Compared with other organ dysfunction, the effect of hepatic injury on mortality rate in intensive care unit patients is controversial. It can be lower [36,39] or higher [35,40-42] than the mortality rate associated with other organ failure. Besides the role of hepatic injury on the mortality rate in septic patients, the importance of preexisting normal hepatic function for the survival rate of these patients is emphasized by the fact that underlying hepatic dysfunction is an important risk factor for prognosis [43]. For example, the mortality rate was 100% in a group of cirrhotic patients requiring mechanical ventilation for septic shock [44]. Additionally, the alteration of hepatic tests observed in humans do not reflect the full spectrum of alterations in hepatic functions encountered in experimental models of sepsis [45-48]. In these experimental models, the modifications of hepatic function during sepsis may be either beneficial (acute-phase protein response, clearance of endotoxin, bacteria, and cytokines) or deleterious (release of oxygen-derived radicals and decrease in cytochrome P-450 activity) and may, in this way, modify the prognosis of the disease. Modifications of Hepatic Function in Experimental Models of Sepsis During experimental sepsis, hepatic plasma concentrations of proteins such as C reactive protein, alpha 1-antitrypsin, and fibrinogen increase [5]. These acute-phase proteins modulate the immunologic functions, repair tissue injury, and have a protective effect on endotoxin- and TNF-alpha-induced injury [4]. An increased transport of amino acids in hepatocytes is necessary to increase the synthesis of these proteins, and endotoxin has been shown to increase hepatic glutamine [49] and arginine [50] transport. In contrast, concentrations of albumin and Hepatic production of urea is also in experimental sepsis by the increased uptake of amino acids after the of proteins in peripheral alterations of glucose have been is increased during sepsis by prostaglandins, and by the increased of amino acid and lactate is because the activity of the enzyme of the is by endotoxin In with the activity is to a of which is the most of and are through than gluconeogenesis Consequently, as glucose becomes severe may may also modify the inflammatory response of the liver in Kupffer cells, the release of is lower when cells are in a than in a normal The of drug biotransformation is encountered during sepsis and NO have been shown to decrease the activity of most cytochrome P-450 enzymes. bile flow and bile the of various (Table Modifications of Hepatic Functions in Experimental Models of liver is a for endotoxin, bacteria, and After an IV injection, most of the endotoxin is by Kupffer cells Hepatocytes can clear and endotoxin in the bile The liver also bacteria from blood and bacterial clearance is modified by the of injection and by preexisting liver disease liver failure after results in a decreased to clear bacteria, which is for by increased function in the and The liver is also a of as well as a for extrahepatic [6]. In injected with endotoxin, the liver is a major of TNF-alpha production Besides endotoxin injection increases the production of in Kupffer cells In to plasma concentrations of TNF-alpha and increased h after whereas the concentrations of the two in isolated Kupffer cells increased as early as 1 h after In the liver, significantly increases h after endotoxin injection, whereas the peaks h Thus, Kupffer cells produce both proinflammatory and The liver also in clearance [6]. Thus, this organ plays a role in the inflammatory response during sepsis by both and During sepsis, oxygen-derived radicals are by the hepatic These radicals are in but may also induce tissue injury. release by the liver is after the IV administration of endotoxin Thus, numerous hepatic cell functions are modified in experimental sepsis. Whether these modifications are beneficial or deleterious on is acute-phase protein response, bacteria and endotoxin and clearance might be beneficial by systemic the other decreased biotransformation and might have deleterious these experimental findings to human sepsis is Hepatic Injury in Experimental Models of into the liver is responsible for hepatic injury in experimental models The of the release of and by Kupffer cells After the of on the activation of in endothelial cells TNF-alpha and are responsible for activation of vascular cell and The increased expression of is in all hepatic cells, whereas the increased expression of vascular cell and is on endothelial cells and Kupffer cells After the activation of these and of occur in sinusoids, but not in as observed in extrahepatic These secrete mediators, and O2-derived Both and Kupffer cells represent a to the of tissue and to be important to hepatic injury of from the circulation by or the deleterious effects of Besides the of other have been in hepatic injury in experimental models of sepsis. Although several authors found a protective effect of NO on liver cell et al. et al. and et al. published results. The role of Kupffer cells in hepatic is by the protective effect of The of Kupffer cells by the hepatic injury induced by in Kupffer cell activation with have similar results acute-phase proteins and can the liver from liver However, these effects observed in experimental studies have not been investigated in humans. Because clinical studies found an increased hepatosplanchnic blood flow associated with mild hepatic injury during sepsis, either the high hepatosplanchnic blood flow is for the regional O2 demand or hepatic dysfunction is not infusion and et al. that, after endotoxin and TNF-alpha perfusion, hepatic cellular dysfunction the of the This early dysfunction after administration, but is unknown. In contrast, using clearance to assess the hepatic et al. that alterations in the concentrations of and which are indicators of cell dysfunction in sepsis, hepatic They that cellular is a than a direct injury induced by Thus, modifications of hepatic function may be the of the direct effect of endotoxin Additionally, hepatic injury may occur after hepatic with cell and enzyme Whether increasing hepatosplanchnic might hepatic function and has not been In patients with sepsis, hepatosplanchnic blood flow increases proportionately to cardiac output, and the fractional hepatosplanchnic blood flow remains constant. Hepatosplanchnic is increased. Although the criteria for hepatic dysfunction and severity must be better clinical studies that hepatic injury is often and the Thus, because increased hepatosplanchnic blood flow is associated with mild hepatic injury, either the hepatic blood flow is for the regional O2 demand or hepatic dysfunction is not Whether increasing hepatosplanchnic might hepatic function and has not been of clinical studies are hepatic arterial and portal vein blood flows are not measured the hepatic is not measured from splanchnic because it is not to from the portal vein. hepatic tests measure cellular injury, but there are few data on the alterations of hepatic In contrast, models of sepsis are numerous but do not always reflect clinical hepatic function modifications have been described in these These changes may be the of the direct effects of endotoxin They also represent a of deleterious consequences on and a protective with beneficial Hepatic may also occur and increase hepatic injury. to experimental clinical are required for a better understanding of the role of the liver in human sepsis.

Advances in preoperative assessment of liver function

Cluster analysis of indicators of liver functional and preoperative low branched-chain amino acid tyrosine ration indicate a high risk of early recurrence in analysis of 165 hepatocellular carcinoma patients after initial hepatectomy

Warm ischemia time-dependent variation in liver damage, inflammation, and function in hepatic ischemia/reperfusion injury

Introduction: Therapy of multidrug-resistant tuberculosis (MDR-TB) patients is still not handled properly, is more toxic, and is more high-priced. The liver is the primary metabolism, and the kidney is the main excretion organ. The study aims to know the association of multidrug-resistant tuberculosis (MDR-TB) patients on profile of liver and kidney function Methods: The research is a cross-sectional study with consecutive sampling. Twenty-four respondents were confirmed as MDR-TB patients without HIV who had done biochemical tests. Results: We found that sex of MDR-TB patients on liver function; ALT (p = 0.124) and AST (p = 0.077) and kidney function; BUN (p = 0.270), creatinine (p = 0.137). Age of MDR-TB patients on liver function; ALT (p = 0.587) and AST (p = 0.093) and kidney function; BUN (p = 0.423), creatinine (p = 0.142). Comorbid on MDR-TB patients on liver function; ALT (p = 0.756) and AST (p = 0.244) and kidney function; BUN (p = 0.816), creatinine (p = 0.612). Conclusions: There were no association in sex, age, and comorbid of MDR-TB on liver and kidney function.

Hemodynamic measurements during organ transplant procedures are essential. In this observational study, we measured clinical and hemodynamic parameters in 11 patients with advanced pulse indicator continuous cardiac output monitoring. Normally distributed clinical data were calculated as means ± standard deviation; hemodynamic, metabolic, and respiratory parameters related to liver and renal function were compared by linear regression analysis using Pearson correlation. Compared with the normal range, systemic vascular resistance was high (2278.02 ± 719.6 dyne·s/cm²/m²) and intrathoracic blood volume was low (787.37 ± 224.01 mL/m²) in our patient group. C-reactive protein and interleukin 6 levels were 96.26 ± 68.10 mg/mL and 246.24 ± 355.74 mmol/L, respectively. Liver and renal function parameters were in normal ranges. Extravascular lung water was correlated with total, conjugated, and unconjugated bilirubin and albumin (r = 0.342/P = .005; r = 0.338/ P = .005; r = 0.394/P = .001, and r = 0.358/P = .003) but not with aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and serum creatinine. Intrathoracic blood volume index was correlated with total bilirubin, unconjugated bilirubin, and albumin (r = 0.324/P = .007; r = 0.394/P = .001, and r = 0.296/P = .015) but not with conjugated bilirubin, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and serum creatinine. Lactate was not correlated with total bilirubin, unconjugated bilirubin, albumin, and serum creatinine, but base excess was correlated with total bilirubin, unconjugated bilirubin, alanine aminotransferase, and albumin. PO₂ and Pco₂ were not correlated with liver function, although PO₂ was correlated with albumin. No correlations were shown between intrathoracic blood volume index, extravascular lung water, and liver function, but metabolic parameters, including base excess and lactate, were correlated with liver function. Pulse indicator continuous cardiac output monitoring may be a useful method to assess organ function and tissue perfusion in organ transplant.

In extended liver resections, the preservation of vascular and biliary structures of the entire remnant liver is of paramount importance. The impact of venous outflow impairment and its consequences for liver regeneration and function are still a matter of debate. Rats (n = 75) were subjected to a 90% partial hepatectomy (PH), to a 70% liver resection with narrowing of the hepatic outflow of an additional 20% parenchyma (70%+ PH) or to an anatomic 70% PH. Postoperatively hepatocyte proliferation (Ki-67), liver function and survival were assessed. Gene expression analysis for markers of regeneration was determined by in-house complementary (DNA) arrays and quantitative real-time polymerase chain reaction (RT-PCR). Ninety percent PH led to a greater regenerative response as shown Ki-67 compared to animals with a 70%+PH (p < 0.05). However, liver function was equally impaired in both groups. Rats with 70% PH showed a greater proliferation index with less hepatic injury and better liver function. While mortality was 0% in the group of 70% PH, rats with 90% PH and 70+PH had a reduced survival of 75% (p < 0.05) Venous outflow obstruction leads to an impairment of liver regeneration and liver function. In cases with critically small liver remnants, restoration of an adequate venous outflow may be mandatory.

2D and 3D liver models

Background: Because of the rapid progression of antiviral treatment options and the increasing frequency of nonviral-related hepatocellular carcinoma (HCC) due to the aging of society, the number of HCC patients with good hepatic function has been increasing and a more detailed method of assessment of hepatic function is needed. The Child-Pugh classification (CP) is used worldwide as an assessment tool for hepatic reserve function, even though it has some weaknesses. Recently, the albumin-bilirubin (ALBI) grade, calculated based on only albumin and total bilirubin, was proposed, and recent investigations have suggested that ALBI grade instead of CP can be used as an assessment tool for hepatic function as part of therapeutic strategies such as Barcelona Clinic Liver Cancer staging and a practical guideline presented by the Japan Society of Hepatology as well for total staging scoring systems. There has been an increasing number of reports showing that it has better capability than CP for HCC patients who undergo not only curative but also palliative treatments. Transcatheter arterial chemoembolization (TACE) is a major palliative treatment used for unresectable HCC, and the idea of TACE-refractory status has been proposed to indicate the possibility of switching to a tyrosine kinase inhibitor (TKI). However, TKI administration requires a maintained hepatic reserve function, thus the importance of assessment of hepatic function in patients undergoing TACE treatments has increased. We consider that ALBI grade might also play a significant role as part of a detailed assessment of relative changes in hepatic function during treatment. In this review, we evaluate the practical usefulness of ALBI grade for assessing hepatic function and HCC prognosis. Key Message: A detailed assessment of hepatic function is required for recent HCC therapeutic strategies. ALBI grade may be a powerful tool to improve treatment options for affected patients.

BackgroundSingle lifestyle, dietary pattern, and liver function are closely associated with cognitive ability, yet their combined influences on cognition remain unclear. This study aimed to investigate the effects of lifestyle, dietary patterns, and liver function on cognitive impairment among older adults.MethodsOne thousand and ninety-six older adults were recruited from communities. Among them, 630 participants completed cognitive function tests. The lifestyle and dietary patterns of the participants were assessed using a healthy lifestyle score (HLS) and a healthy dietary score (HDS). Liver function was assessed using four predictive indicators: AST/HDL-C, ALT/HDL-C, HSI, and ZJU. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA). Logistic regression, receiver operating characteristic curves (ROC), and restricted cubic splines (RCS) were applied to explore the relationship between variables.ResultsA significant negative correlation was observed between HLS and liver function indicators (rAST/HDL-C = −0.156, rZJU = −0.270, both p < 0.001), whereas a significant positive correlation was identified between HDS and MoCA scores (r = 0.074, p < 0.05). Poor liver function, represented by elevated plasma AST/HDL-C, was associated with increased mild cognitive impairment (MCI) risk (OR = 1.029, p = 0.007). ROC analysis showed that plasma AST/HDL-C had the highest predictive power for MCI (AUC = 0.634). RCS analysis revealed that AST/HDL-C and ALT/HDL-C were positively correlated with the risk of MCI, with cut-off values of 14.1 and 10.1, respectively.ConclusionImpaired liver function is strongly associated with cognitive impairment, highlighting the critical role of maintaining healthy liver function in preventing MCI in the elderly. A healthy lifestyle positively correlated with both liver and cognitive functions, and a balanced diet significantly improved cognitive outcomes.

BackgroundSarcopenia, obesity and sarcopenic obesity have been linked to impaired outcome after liver surgery. Preoperative liver function of sarcopenic, obese and sarcopenic-obese patients might be reduced, possibly leading to more post-operative morbidity. The aim of this study was to explore whether liver function and volume were influenced by body composition in patients undergoing liver resection.MethodsIn 2011 and 2012, all consecutive patients undergoing the methacetin breath liver function test were included. Liver volumetry and muscle mass analysis were performed using preoperative CT scans and Osirix® software. Muscle mass and body-fat% were calculated. Predefined cut-off values for sarcopenia and the top two body-fat% quintiles were used to identify sarcopenia and obesity, respectively. Histologic assessment of the resected liver gave insight in background liver disease.ResultsA total number of 80 patients were included. Liver function and volume were comparable in sarcopenic(-obese) and non-sarcopenic(-obese) patients. Obese patients showed significantly reduced liver function [295 (95–508) vs. 358 (96–684) µg/kg/h, P = 0.018] and a trend towards larger liver size [1694 (1116–2685) vs. 1533 (869–2852) mL, P = 0.079] compared with non-obese patients. Weight (r = −0.40), body surface area (r = −0.32), estimated body-fat% (r = −0.43) and body mass index (r = −0.47) showed a weak but significant negative (all P < 0.05) correlation with liver function. Moreover, body-fat% was identified as an independent factor negatively affecting the liver function.ConclusionSarcopenia and sarcopenic obesity did not seem to influence liver size and function negatively. However, obese patients had larger, although less functional, livers, indicating dissociation of liver function and volume in these patients.

To the Editor, In a recently published survey of 100 liver centers, Breitenstein et al. [1] reported that on a global scale, (1) the average minimal remnant liver volume for resection is 25% (range = 15-40%) for normal liver parenchyma and 50% (range = 25–90%) for cirrhotic livers, (2) portal vein occlusion is employed in 89% of the centers for purposes of augmenting liver volume before surgery, and that (3) 38% of the centers employed liver function tests as part of their clinical routine, of which 76% used the ICG clearance test. The interesting survey provoked a few issues that we feel obliged to address. The authors contend that “below a certain volume, a remnant liver cannot sustain metabolic, synthetic, and detoxifying functions” [1]—a statement that is unequivocal and uncontested. However, it should be born in mind that liver volume is not a directly proportional measure of liver function. We have demonstrated a few fundamental aspects of the volume-function relationship that support this notion: (i) Whereas liver function correlates with volume in uncompromised livers [2], there is significantly less correlation between liver volume and function in patients with coexisting parenchymal liver disease [3, 4]. (ii) This discrepancy also applies to the regenerating liver [3]. (iii) The liver often exhibits functional heterogeneity [3]. These findings have been corroborated to some extent by others [5]. Consequently, a marginal remnant liver volume (e.g., 25% for cirrhotic livers [1]) may translate to functional deficiencies following resection and hence predisposes the organ to the “small-for-size” or, rather, the “small-for-function” syndrome. Likewise, allowing the organ to regenerate to a predetermined volume before resection bears comparable implications and strongly pleads for the use of dynamic liver function tests rather than CT volumetry as the gold standard, particularly for borderline surgical decisions. We emphasize specifically the use of quantitative dynamic liver function tests [i.e., ICG clearance, 99mTc-mebrofenin hepatobiliary scintigraphy (HBS) [2–4], galactose elimination capacity (GEC) [5], and 99mTc-labeled galactosyl human serum albumin scintigraphy (GSAS)] inasmuch as conventional liver function tests such as prothrombin time, serum bilirubin, and the Child-Pugh score are relatively insensitive and are thus lagging indicators for determining whether a liver resection can be safely performed. It is well known that there are notable discrepancies between the above-mentioned dynamic liver function tests in the assessment of liver function. In our patient population, ICG and 99mTc-mebrofenin uptake exhibited similar pharmacokinetics in regenerating rat livers (that also corresponded well to the extent of hepatic damage), whereas the GSAS and GEC tests displayed an underestimation and an overestimation, respectively, of liver function in comparison to ICG and 99mTc-mebrofenin uptake (unpublished). This is because liver function encompasses a broad spectrum of processes, ranging from uptake, synthesis, biotransformation, and systemic and canalicular secretion, whereby each test measures a different component of that spectrum. In summary, criteria on the basis of which extended liver resections are performed should preferably be dictated by functional parameters rather than volume alone, especially when livers are resected to a minimally accepted remnant volume. Furthermore, we advocate the use of dynamic liver function tests such as ICG or 99mTc-mebrofenin uptake for testing liver function due to their sensitivity and prognostic strength. We acknowledge that each of these tests reflects a limited aspect of liver function only. However, currently no better, clinically viable alternatives are available.

Non-invasive evaluation of liver function in small animal models remains a challenge. Hepatobiliary scintigraphy (HBS) enables the assessment of total and regional liver function for both uptake and excretion in larger species. To validate quantitative liver function assessment with dedicated pinhole HBS in rats. To illustrate an application of this technique, liver function was assessed in two surgical models of liver regeneration. HBS was performed in 12 rats with 99mTc-mebrofenin on a dedicated animal pinhole gamma camera. The hepatic uptake rate was calculated twice by different observers to establish a normal range and the reproducibility of processing. The degree of hepatocellular injury and synthesis function were assessed by serum liver tests. Liver function was compared with liver weight. Subsequently, three groups of three rats were scanned on three separate days to assess the reproducibility of HBS. Finally, to illustrate an application of this technique, liver function was assessed in two surgical models of liver regeneration. HBS in rats was feasible without mortality. The mean liver uptake rate was 77.29+/-1.29% . min(-1). Calculation of the liver uptake (% . min(-1)) was highly reproducible (r=0.95, P<0.001). There was a good correlation between liver weight and function measured by HBS at baseline and after partial resection (r=0.94, P<0.001). HBS offers a unique combination of functional liver uptake and excretion assessment with the ability to determine the liver function reserve before and after an intervention in rats.

An optimization model based upon multivariate analysis was developed to capture hepatic specific function in relation to the environmental condition and the intracellular metabolic network and the flux information obtained from metabolic flux analysis (MFA). Fisher discriminant analysis (FDA) was applied to maximize the discrimination among groups thus permitting visualization of the sample separation between different conditions. FDA identified factors that contribute greatly to the separation of the groups. Mapping fluxes to a hepatic function permits an examination of the interrelationship of the fluxes and captures the hepatic function in terms of the metabolic profile. Partial least square (PLS) was the mapping technique applied to evaluate the effect of metabolic state on hepatic function, namely, the levels of intracellular triglyceride or urea production. This methodology identified fluxes most relevant to minimizing the accumulation of intracellular triglyceride and maximizing the production of urea, two important hepatic functions. In the study, 75 metabolic fluxes were mapped to measured levels of intracellular triglyceride or urea. Once a mapping model was constructed, analyzing the model parameters permitted the assessment of how the metabolic profile, in turn, pathways collectively regulate and control hepatic function by identifying pathways that are highly correlated with the hepatic function.