Indocyanine Green Clearance Research Articles

55 POSTER Cell surface proteomic analysis of human renal tumor endothelium

Although indocyanine green (ICG) has promising applications in photothermal therapy (PPT) because of its low toxicity and high efficiency in inducing heat and singlet oxygen formation in response to near-infrared light with a wavelength of approximately 800 nm, its clinical application has been restricted because of its rapid body clearance and poor water stability. Therefore, cell membrane capsules (CMCs) derived from mammalian cells were used to encapsulate negatively charged ICG by temporarily permeating the plasma membrane and resealing using positively charged doxorubicin hydrochloride (DOX). The resulting [email protected]/ICG exhibited a spherical shape, with a diameter of approximately 800 nm. The DOX and ICG encapsulation was confirmed by the UV–vis spectrum; a very small amount of DOX (0.8 μg) and a very high amount of ICG (∼110 μg) were encapsulated in 200 μg CMCs. Encapsulation in the CMCs leads to sustained release of ICG, especially in the presence of positively charged DOX. The temperature enhancement and generation of ROS by ICG encapsulated in CMCs were confirmed upon laser irradiation in vitro, leading to cell death. [email protected]/ICG also can significantly enhance the retention of ICG in a tumor after intratumoral injection in vivo. As a result, combination treatment with [email protected]/ICG and laser irradiation demonstrated much better anticancer efficacy than that of free DOX/ICG and [email protected] The encapsulation of ICG into CMCs, especially with the assistance of DOX, significantly slows down the body clearance of ICG, with a retained PPT effect against tumors, an important step forward in the practical application of ICG in cancer therapy.In this study, cell membrane capsules (CMCs) derived from mammalian cells were used to encapsulate negatively charged indocyanine green (ICG) by temporarily permeating the plasma membrane and resealing, in the presence of positively charged doxorubicin hydrochloride (DOX). The resulting [email protected]/ICG exhibited a spherical shape, with a diameter of approximately 800 nm. Encapsulation in the CMCs leads to sustained release of ICG and thus slower clearance inside body, especially in the presence of positively charged DOX. The system provides a better photothermal effect against tumors, an important step forward in the practical application of ICG in cancer therapy.

The Adaptive Response of the Reticuloendothelial System to Major Liver Resection in Humans

To evaluate the contribution of the liver to total circulatory reticuloendothelial system (RES) phagocytosis capacity in patients undergoing liver resection and to compare it with values in end-stage chronic liver disease. The mechanism whereby major liver resection is associated with a high incidence of infection is unknown. Significant impairment of RES phagocytosis has been described in liver failure, rendering such patients susceptible to infection; and we hypothesized that similar impairment might occur following major liver resection. A prospective study was conducted in which Tc-albumin microspheres blood clearance served as a parameter for RES phagocytosis and was studied together with indocyanine green blood clearance, actual liver volume measured by three-dimensional image analysis, and a clinical score of hepatic dysfunction in 17 patients undergoing liver resection and in 8 patients with end-stage chronic liver disease assessed for liver transplantation. When expressed relative to volume unit of residual liver, microspheres clearance increased significantly in the immediate postoperative period (day 1) following major (0.009% versus 0.022% min(-1) mL(-1), P < 0.001), but not minor liver resection. In contrast, the absolute rate of microsphere clearance decreased following major resection (15% min(-1) versus 10% min(-1), P < 0.001) and was comparable with the rate observed in end-stage chronic liver disease (9% min(-1)). This decrease in circulatory microspheres clearance after resection paralleled a decrease in indocyanine green clearance (R2 = 0.511, P = 0.006), and there was a trend for those with moderate liver dysfunction to have lower microspheres clearance rates (P = 0.068). Preservation of a minimum volume of functioning liver is a prerequisite for adequate RES phagocytosis capacity, and failure of this system may predispose patients undergoing major liver resection to infection as observed in clinical studies.

Relation between indocyanine green (ICG) plasma disappearance rate and ICG blood clearance in critically ill patients

In contrast to indocyanine green (ICG) blood clearance, the plasma disappearance rate (PDR) of ICG does not require absolute ICG blood concentrations and today can be assessed transcutaneously. In this study, we analyzed the relation between ICG disappearance rate and ICG blood clearance as parameters of liver function in critically patients. Observational, clinical study. Retrospective analysis. Operative intensive care unit of a university hospital. 209 patients (139 male, 70 female, age 10-88 years, 53+/-19 years) who underwent liver function monitoring for clinical indication. Patients suffered from sepsis (n=99), acute respiratory distress syndrome (n=31), severe head injury (n=38), hemorrhagic shock (n=19), intracranial hemorrhage (n=19), and cerebral infarction (n=3). All patients were sedated and mechanically ventilated via an endotracheal tube. All patients were monitored by the transpulmonary double-indicator (thermo-dye dilution) technique using a thermistor and calibrated fiber-optic system (Pulsiocath 4F, PV 2024L, Pulsion Medical Systems, Munich, Germany). For each measurement, a dosage of 0.3 mg/kg ICG was injected central-venously. Transpulmonary ICG concentration curves were analyzed automatically using a computer system (COLD-Z021, Pulsion Medical Systems, Munich, Germany). By using the first ICG measurement in each patient after admission to the ICU, we analyzed 209 pairs of ICG disappearance rate and ICG blood clearance. Linear regression analysis revealed a correlation of r2=0.77 between ICG-PDR and ICG blood clearance. ICG-PDR does reflect ICG blood clearance with sufficient accuracy in critically ill patients and may be used as a surrogate.

Two Hundred Forty Consecutive Portal Vein Embolizations Before Extended Hepatectomy for Biliary Cancer

To assess clinical benefit of portal vein embolization (PVE) before extended, complex hepatectomy for biliary cancer. Many investigators have addressed clinical utility of PVE before simple hepatectomy for metastatic liver cancer or hepatocellular carcinoma, but few have reported PVE before hepatectomy for biliary cancer due to the limited number of surgical cases. This study involved 240 consecutive patients with biliary cancer (150 cholangiocarcinomas and 90 gallbladder cancers) who underwent PVE before an extended hepatectomy (right or left trisectionectomy or right hepatectomy). All PVEs were performed by the "ipsilateral approach" 2 to 3 weeks before surgery. Hepatic volume and function changes after PVE were analyzed, and the outcome also was reviewed. There were no procedure-related complications requiring blood transfusion or interventions. Of the 240 patients, 47 (19.6%) did not undergo subsequent hepatectomy. The incidence of unresectability was higher in gallbladder cancer than in cholangiocarcinoma (32.2% versus 12.0%, P < 0.005). The remaining 193 patients (132 cholangiocarcinomas and 61 gallbladder cancers) underwent hepatectomy with resection of the caudate lobe and extrahepatic bile duct (n = 187), pancreatoduodenectomy (n = 42), and/or portal vein resection (n = 63). Seventeen (8.8%) patients died of postoperative complications: mortality was higher in gallbladder cancer than in cholangiocarcinoma (18.0% versus 4.5%, P < 0.05); and it was also higher in patients whose indocyanine green clearance (KICG) of the future liver remnant after PVE was <0.05 than those whose index was >or=0.05 (28.6% versus 5.5%, P < 0.001). The 3- and 5-year survival after hepatectomy was 41.7% and 26.8% in cholangiocarcinoma and 25.3% and 17.1% in gallbladder cancer, respectively (P = 0.011). In 136 other patients with cholangiocarcinoma who underwent a less than 50% resection of the liver without PVE, a mortality of 3.7% and a 5-year survival of 27.6% were observed, which was similar to the 132 patients with cholangiocarcinoma who underwent extended hepatectomy after PVE. PVE has the potential benefit for patients with advanced biliary cancer who are to undergo extended, complex hepatectomy. Along with the use of PVE, further improvements in surgical techniques and refinements in perioperative management are necessary to make difficult hepatobiliary resections safer.

Perioperative real-time monitoring of indocyanine green clearance by pulse spectrophotometry predicts remnant liver functional reserve in resection of hepatocellular carcinoma

There is no standard method for predicting remnant liver functional reserve after hepatectomy or for monitoring it in real time. Indocyanine green (ICG) clearance (K) was measured non-invasively and instantaneously using pulse spectrophotometry before surgery, during inflow occlusion and after hepatectomy in 75 patients who underwent anatomical liver resection for hepatocellular carcinoma (HCC). Eight patients (11 per cent) suffered liver failure and one (1 per cent) died in hospital. An estimated remnant K value of 0.090 per min was the cut-off value for liver failure. In a logistic regression model, the estimated remnant K (0.090 per min; P = 0.022) and age (65 years; P = 0.025) were significant predictors of postoperative liver failure. There was a correlation between the estimated and measured post-hepatectomy K, and between the inflow occlusion K and measured post-hepatectomy K (P < 0.001). The cut-off value of less than 0.090 per min for the estimated remnant K resulted in 88 per cent sensitivity and 82 per cent specificity for predicting liver failure. Perioperative real-time monitoring of ICG-K is useful for evaluating the remnant liver functional reserve before, during and after liver resection for HCC. The estimated remnant K is a significant predictor of liver failure.

Indocyanine green clearance as a predictor of outcome in liver transplant patients

Invasive measurement of indocyanine green clearance (ICG) has been shown to predict the outcome after liver transplantation in a small series of patients. A non-invasive technique using ICG plasma disappearance rate (PDR) has recently been shown to correlate well with invasive techniques. We report our experience of ICG PDR in a large cohort of liver transplant patients.

Establishment of an indocyanine green test using an automatic chemistry analyzer

The indocyanine green (ICG) clearance test has been used to assess the reserve of hepatic function. This method is based on the spectrometric measurement of its plasma concentration at maximum wavelength of 805 nm, which requires a spectrophotometer and associated maintenance. We established an ICG clearance test using a Toshiba 200FR automatic chemistry analyzer that can be tuned to a wavelength of approximately 805 nm. Five pooled sera spiked from 0 to 4.0 mg/dL were analyzed for linearity test and precision was determined at five levels in the range 0.1-2.0 mg/dL. The ICG retention rate at 15 min (R15) was determined for 38 patients using a conventional method and our method. The ICG clearance test using the automatic chemistry analyzer showed good linearity, and precision ranged from 0.3% to 1.0% for within-run CVs and from 0.6% to 4.7% for total CVs. The degree of agreement between the two methods was also acceptable (mean difference of 1.5%). It is expected that the ICG test using the automatic chemistry analyzer can replace the conventional ICG clearance test, considering the excellent agreement, good precision and linearity over a clinically relevant range.

Antihepatitis C virus status in hepatocellular carcinoma and the influence on clinicopathological findings and operative results.

Antihepatitis C virus (HCV) status was investigated in 100 patients undergoing hepatectomy for hepatocellular carcinoma (HCC) between 1980 and 1989. The clinicopathological findings and operative results, in patients with or without HCV marker, were compared retrospectively. The positivity rate of anti-HCV was 51 per cent. In this group there was a higher mean age, fewer symptoms, raised alanine aminotransferase level, higher 15-min indocyanine green clearance rate and earlier tumour stage compared with the anti-HCV negative group. Positive tumour margins and vascular invasion were seen less frequently in the anti-HCV positive group. HCC with HCV marker showed characteristic features of chronic non-A non-B hepatitis and of HCC originating from liver cirrhosis. There was a better cumulative 1-year survival rate for anti-HCV positive patients, but 3- and 5-year survival rates after hepatectomy were similar in both groups. Although HCV-related HCC had typical features of chronic non-A non-B hepatitis and a relatively early stage of tumour, biological features and operative results were similar with or without the HCV marker.

Monitoring global volume-related hemodynamic or regional variables after initial resuscitation: What is a better predictor of outcome in critically ill septic patients?*

Regional variables of organ dysfunction are thought to be better monitoring variables than global pressure-related hemodynamic variables. Whether a difference exists between regional and global volume-related variables in critically ill patients after resuscitation is unknown. Prospective diagnostic test evaluation. University-affiliated mixed intensive care unit. Twenty-eight critically ill patients. Using standardized resuscitation, hemodynamic optimization was targeted at mean arterial pressure, heart rate, occlusion pressure, cardiac output, systemic vascular resistance, and urine output. Primary outcome variable was in-hospital mortality. During resuscitation, global volume-related hemodynamic variables were measured simultaneously and compared with regional variables. At admission no variable was superior as a predictor of outcome. During resuscitation, significant changes were seen in mean arterial pressure, central venous pressure, oxygen delivery, systemic vascular resistance, total blood volume, right heart and ventricle end-diastolic volume, right ventricle ejection fraction, right and left stroke work index, intramucosal carbon dioxide pressure, gastric mucosal pH, mucosal-end tidal Pco2 gap, indocyanine green blood clearance, indocyanine green plasma clearance, and plasma disappearance rate. Multivariate analysis identified lactate, gastric mucosal pH, mucosal-end tidal Pco2 gap, mucosal-arterial Pco2 gap, indocyanine green plasma clearance, and plasma disappearance rate of dye as nondependent predictors of outcome. Patients who subsequently died had a significantly lower gastric mucosal pH, higher intramucosal carbon dioxide pressure and mucosal-end tidal Pco2 gap, and lower indocyanine green blood clearance, indocyanine green plasma clearance, plasma disappearance rate, and right ventricular end-diastolic volume index, of which gastric mucosal pH, mucosal-end tidal Pco2 gap, and indocyanine green blood clearance were the most important predictors of outcome. Initial resuscitation of critically ill patients with shock does not require monitoring of regional variables. After stabilization, however, regional variables are the best predictors of outcome.

Estradiol improves cardiac and hepatic function after trauma-hemorrhage: role of enhanced heat shock protein expression

Although studies indicate that 17beta-estradiol administration after trauma-hemorrhage (T-H) improves cardiac and hepatic functions, the underlying mechanisms remain unclear. Because the induction of heat shock proteins (HSPs) can protect cardiac and hepatic functions, we hypothesized that these proteins contribute to the salutary effects of estradiol after T-H. To test this hypothesis, male Sprague-Dawley rats ( approximately 300 g) underwent laparotomy and hemorrhagic shock (35-40 mmHg for approximately 90 min) followed by resuscitation with four times the shed blood volume in the form of Ringer lactate. 17beta-estradiol (1 mg/kg body wt) was administered at the end of the resuscitation. Five hours after T-H and resuscitation there was a significant decrease in cardiac output, positive and negative maximal rate of left ventricular pressure. Liver function as determined by bile production and indocyanine green clearance was also compromised after T-H and resuscitation. This was accompanied by an increase in plasma alanine aminotransferase (ALT) levels and liver perfusate lactic dehydrogenase levels. Furthermore, circulating levels of TNF-alpha, IL-6, and IL-10 were also increased. In addition to decreased cardiac and hepatic function, there was an increase in cardiac HSP32 expression and a reduction in HSP60 expression after T-H. In the liver, HSP32 and HSP70 were increased after T-H. There was no change in heart HSP70 and liver HSP60 after T-H and resuscitation. Estradiol administration at the end of T-H and resuscitation increased heart/liver HSPs expression, ameliorated the impairment of heart/liver functions, and significantly prevented the increase in plasma levels of ALT, TNF-alpha, and IL-6. The ability of estradiol to induce HSPs expression in the heart and the liver suggests that HSPs, in part, mediate the salutary effects of 17beta-estradiol on organ functions after T-H.

Der Einfluss des kontinuierlich positiven Atemwegsdruckes (CPAP) auf die Blutflussgeschwindigkeit im venösen Leberstromgebiet - duplexsonographische Untersuchungen

In the last years, noninvasive techniques of artificial ventilation like continuous positive airway pressure (CPAP) have become more and more important. However, the effects of such procedures on the circulation of the hepatosplanchnic area are, except for the indocyanine green plasma clearance, not yet representative by means of noninvasive investigation methods. We studied maximum blood flow velocity in defined areas of hepatic and portal veins by duplex ultrasonography in 20 healthy volunteers (12 male, 8 female; age: 24,7 +/- 4,7 years [mean +/- SD]) before, during and after application of CPAP (10 cm H(2)O). As many measurements as possible were taken in both vascular systems. After division into five minute intervals arithmetical mean values were calculated for each interval. The experiment was divided into a control interval ("before CPAP"), three "CPAP" intervals and finally two "after CPAP" intervals. Heart rate and blood pressure were taken at the beginning of these intervals. Compared with the control interval, maximum blood flow velocity in the area of the hepatic vein decreased significantly by 13,2 %, 16,8 % and 15,7 % (p < or = 0,001 in each case) during each of the three "CPAP" periods. In the portal venous area blood flow velocity decreased by 4,3 %, 8,8 % and 7,0 %, respectively, with a significant decrease only in the second "CPAP" interval (p < or = 0,005). After CPAP, changes returned to baseline within a few minutes. Heart rate and blood pressure showed no significant differences during the whole experiment. Parameters taken in both venous vascular areas of the liver show clear correspondence with the results of former studies, which have been determined by means of more invasive investigation methods. Maximum blood flow velocity seems to be useful for monitoring liver blood flow and its individual time course during CPAP, noninvasively and semiquantitatively. Further trials under conditions of controlled mechanical ventilation should be performed to optimize ventilation strategies for the critically ill.

Neutral endopeptidase (EC 3.4.24.11) in cirrhotic liver: A new target to treat portal hypertension?

In liver cirrhosis atrial natriuretic peptide (ANP) decreases portal vascular resistance and tributary flow. The enzyme neutral endopeptidase (NEP) degrades ANP and bradykinin and generates endothelin-1 from big-endothelin. We determined the effects of NEP inhibition by candoxatrilat on hormonal status, liver function and arterial and portal pressures in rats with CCl4-induced cirrhosis. Two groups of seven control rats received 1 ml 5% glucose solution alone or containing 10 mg/kg candoxatrilat; three groups of 10 ascitic cirrhotic rats received placebo, 5 or 10 mg/kg candoxatrilat. NEP protein concentration and immunostaining were analyzed in normal and cirrhotic livers. In cirrhotic rats 10 mg/kg candoxatrilat significantly increased steady-state indocyanine green clearance (a parameter reflecting liver plasma flow) (P<0.01), decreased portal pressure (P<0.01), had no effect on arterial pressure and plasma renin activity but increased ANP plasma levels (P<0.05) and urinary excretions (P<0.01) of ANP and cGMP. In the cytosol fraction of rat cirrhotic livers a 280% increase in NEP content was found (P<0.01), chiefly localized in desmin-positive myofibroblast-like cells of fibrous septa. Candoxatrilat has few effects on systemic hemodynamics and hormonal status; its portal hypotensive action depends on effects exerted on intrahepatic vascular resistance.

Prolonged Q–Tc interval in mild portal hypertensive cirrhosis

The Q-T(c) interval is prolonged in a substantial fraction of patients with cirrhosis, thus indicating delayed repolarisation. However, no information is available in mild portal hypertensive patients. We therefore determined the Q-T(c) interval in cirrhotic patients with hepatic venous pressure gradient (HVPG) < 12 mmHg. Forty-four patients with cirrhosis and HVPG < 12 mmHg underwent a haemodynamic study. They were compared with 36 cirrhotic patients with clinically significant portal hypertension (HVPG> or = 12 mmHg) and controls without liver disease. The fraction with prolonged Q-T(c) interval (> 0.440 s(1/2)) was similar in the two cirrhotic groups (49 vs 50%, ns) and significantly above that of the controls (5%, P < 0.005). Q-T(c) was normal in patients with normal HVPG. Likewise, mean Q-T(c) was 0.449 and 0.447 s(1/2) in the two cirrhotic groups (ns), values which are significantly above that of the controls (0.410 s(1/2), P < 0.01). In the mild portal hypertensive group, the Q-T(c) interval was inversely related to indicators of liver function, such as indocyanine green clearance (r = -0.34, P < 0.02). Delayed repolarisation of the myocardium already occurs in a substantial fraction of patients with cirrhosis with only a mild increase in portal pressure. The prolonged Q-T(c) interval may be related to liver dysfunction and to the presence of portal hypertension.

Liver failure

Liver failure is a rare but life-threatening condition affecting a multitude of other organ systems, most notably the brain and kidneys, following severe hepatocellular injury. Liver failure may develop in the absence ('acute') or presence ('acute-on-chronic') of liver disease with substantial differences in pathophysiology and therapeutic options. Within the last 12 months substantial progress has been made in identifying patients who will potentially benefit from extracorporeal support of their failing liver. In addition to traditional 'static' laboratory tests to assess liver function, the significance of 'dynamic' tests, such as indocyanine green clearance, has been better defined, and these tests are becoming more easily available. Transplantation remains the treatment of choice for fulminant, acute and subacute liver failure with predicted unfavorable outcome according to King's College or Clichy criteria, most notably in the absence of pre-existing liver disease, and should be performed before extrahepatic complications emerge. Encouraging results have been obtained with the use of support systems in patients with acute and acute-on-chronic liver failure in relatively small patient collectives, making well-conducted randomized trials a necessity to define their role in this high-risk population. Current (pre)clinical data suggest that programmed cell death is an important mechanism for the pathogenesis of acute and acute-on-chronic liver failure and, thus, antiapoptotic strategies are promising pharmacologically. Although mortality remains high, substantial progress has been made in 2004 regarding the understanding of pathophysiology, and the monitoring and support of the patient presenting with a failing liver.

Improvement of Liver Function After Surgery for Budd-Chiari Syndrome

We evaluated the relationship between liver histology and postoperative improvement of liver function after surgery for Budd-Chiari syndrome (BCS). Over a period of 23 years, we operated on 46 patients with BCS by reconstructing the occluded inferior vena cava (IVC) and reopening as many occluded hepatic veins as possible. We divided the patients into a liver cirrhosis group (group I, n = 30) and a hepatic fibrosis or liver congestion group (group II, n = 16), and compared the ages, duration of illness, preoperative liver function, changes in liver function, and changes in esophageal varices (EV). There were no hospital deaths. In group I the patients were older, and the duration of illness was longer. The group I patients also had a lower thrombotest percentage and a higher serum ammonia. The indocyanine green clearance (ICG) test showed more remarkable improvement in liver function in group II. The rate of disappearance of EV was also higher in group II. Surgery during the early stage of BCS is important in improving postoperative liver function.

Effects of posture (P) induced changes in hepatic blood flow (HBF) and plasma protein binding (PB) on the clearance (CL) of the intravenous (IV) cytochrome P450 3A (CYP3A) biomarker midazolam (MDZ)

Background Use of IV MDZ as a CYP3A probe assumes MDZ CL accurately reflects hepatic CYP3A activity. Because MDZ is a moderate hepatic extraction drug, P induced changes in HBF and/or MDZ plasma PB may affect MDZ CL. Methods 15 healthy, nonsmoking subjects were randomized to a crossover study of supine or ambulant (sitting, standing, walking) P. Fasting subjects received MDZ 0.025 mg/kg IV push and indocyanine green (ICG) 0.5 mg/kg IV to quantify HBF. 18 plasma samples were collected over 6 hr and analyzed by LC/MS/MS (MDZ), HPLC/UV (ICG), and ultra filtration (free MDZ; protein binding). Least squares geometric mean ratios (LS-GMR) and 90% CIs were compared by P. A paired t-test compared free MDZ concentrations and MDZ free fraction by P. Results 13 subjects (7 women) completed the study. (see Table) Correlation of MDZ CL and ICG CL in supine P was r=0.6 (p≤0.05) and ambulant P was r=0.11 (p=0.72). MDZ free fraction 30 min post MDZ and 3 min post ICG were not related to posture (p>0.05). Total MDZ CL did not correlate to MDZ free fraction (r=0.17; p=0.41). Conclusions P induced changes in HBF were minimal and thus the effect of HBF on MDZ CL was not seen. No relationship was observed between MDZ free fraction and MDZ CL. Clinical Pharmacology & Therapeutics (2005) 77, P33–P33; doi: 10.1016/j.clpt.2004.12.017 GM Supine GM Ambulant LS-GMR 90% CI ICG CL (mL/min) 617.8 605.9 0.98 0.86–1.1 MDZ CL (mL/min) 595.6 565.1 0.95 0.88–1.02 GM (SD) GM (SD) p-value Free MDZ (ng/mL)30 min post MPZ 0.25 (0.2, 0.3) 0.28 (0.21, 0.36) p = 0.07 Free MDZ (ng/mL)3 min post ICG 0.16 (0.13, 0.2) 0.16 (0.12, 0.23) p = 0.81

Assessment of hepatic reserve for indication of hepatic resection: how I do it

The perioperative outcome of hepatic resection has improved remarkably in recent years with improved surgical techniques and perioperative care. As a result, the indications of hepatic resection have been extended to include patients with borderline liver function, especially those with associated cirrhosis. For such patients, proper preoperative assessment of liver function reserve is essential to ensure a low incidence of postoperative liver failure and mortality. In our center, routine preoperative assessment of hepatic function reserve in all patients includes clinical assessment, liver biochemistry, coagulation profile, platelet count, and Child-Pugh classification. The indocyanine green clearance test is routinely performed for patients with chronic liver disease. For patients with cirrhosis undergoing major hepatectomy, computed tomography volumetry and laparoscopy are helpful in evaluating whether the remnant liver volume is adequate. In selected patients with small remnant liver, preoperative portal vein embolization can be employed to induce hypertrophy of the remnant liver even in the presence of chronic hepatitis and mild cirrhosis. Careful assessment of comorbid conditions of patients and meticulous surgical techniques to reduce bleeding and hypoxic injury to the remnant liver are complementary to the selection of patients with adequate liver function reserve, to minimize operative mortality.

Effect of 2-methylaminoethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxybiphenyl-2-carboxylic acid-2′-carboxylate monohydrochloride (DDB-S) on indocyanine Green (ICG) clearance in rats

The clearance of ICG, a known hepatic blood flow marker was investigated in rats in order to examine whether DDB-S influences hepatic blood flow. The effect of DDB-S on the protein binding and blood-to-plasma partition of ICG was measured. The steady-state plasma concentration of ICG was monitored before and after co-administration of various concentration of DDB-S, and ICG clearance was estimated from the steady-state concentration and the infusion rate of ICG. There was no significant difference in protein binding and blood-to-plasma partition of ICG with and without addition of DDB-S (10, 20, and 40 microg/mL). When ICG was infused into DDB-S pretreated rats, the steady-state concentrations of ICG decreased and the calculated ICG clearance increased. However, no dose-dependency of ICG Css on DDB-S Css was observed. Since DDB-S did not affect the protein binding and blood-to-plasma partition of ICG, the increased clearance of ICG with co-administration of DDB-S seems to be due to the increased hepatic blood flow by DDB-S.

Improvement of quantitative testing of liver function in patients with chronic hepatitis C after installment of antiviral therapy

To investigate if and to what extent antiviral therapy influenced a broad panel of quantitative testing of liver function (QTLF). Fifty patients with chronic hepatitis C were either treated with interferon (n = 8), interferon/ribavirin (n = 19) or peg-interferon/ribavirin (n = 23). Quantitative testing of liver function, including aminopyrine breath test (ABT), galactose elimination capacity (GEC), sorbitol clearance (SCl) and indocyanine green clearance (ICG) was performed before and 3 mo after initiation of antiviral therapy. After 3 mo of antiviral treatment, 36 patients showed normal transaminases and were negative for HCV-RNA, 14 patients did not respond to therapy. ABT and GEC as parameters of microsomal and cytosolic liver function were reduced in all patients before therapy initiation and returned to normal values in the 36 therapy responders after 3 mo. Parameters of liver perfusion (SCl and ICG) were not affected by antiviral therapy. In the 14 non-responders, no changes in QTLF values were observed during the treatment period. ICG and SCl remained unaffected in patients with chronic hepatitis C, while ABT and GEC were significantly compromised. ABT and GEC normalized in responders to antiviral therapy. Early determination of ABT and GEC may differentiate responders from non-responders to antiviral treatment in hepatitis C.

Nitric-oxide-lowering effect of terlipressin in decompensated cirrhosis

Systemic vasodilatation and arterial hypotension, refractory to adrenergic vasopressors, portend a poor prognosis in patients with decompensated cirrhosis. The production of large amounts of nitric oxide, consequent to endotoxin-induced tumour necrosis factor (TNF)-alpha-mediated upregulation of inducible nitric oxide synthase (iNOS), has been suggested to be central to this phenomenon. Terlipressin has recently been shown in an animal model of cirrhosis to suppress endotoxin-induced TNF-alpha-mediated upregulation of iNOS, thereby preventing overproduction of nitric oxide and restoring normal vascular tone. We present the first evidence that this effect of terlipressin may also occur clinically, in a patient with Child-Pugh class C cirrhosis, endotoxaemia, a raised circulating TNF-alpha concentration, and marked systemic vasodilatation with refractory arterial hypotension. Beneficial effects of terlipressin on circulating nitrate and nitrite concentrations, haemodynamic status, plasma renin levels and indocyanine green clearance were comparable to those of the molecular adsorbent recirculating system (MARS). Our findings suggest that terlipressin may be the vasopressor agent of choice in patients with decompensated cirrhosis and provide a rationale for combination terlipressin and MARS therapy when the therapeutic response to either treatment alone is suboptimal.