Arno Nordin

High Mobility Group Box 1 Protein as a Marker of Hepatocellular Injury in Human Liver Transplantation

High mobility group box 1 protein (HMGB1), a cytokine actively secreted by phagocytes and passively released from necrotic cells, is an inflammatory mediator in experimental hepatic ischemia/reperfusion injury. We characterized its expression in human liver transplantation. In 20 patients, in addition to systemic samples, blood was drawn from portal and hepatic veins during and after reperfusion to assess changes within the graft. Plasma HMGB1, tumor necrosis factor α (TNF‐α), and interleukin‐6 (IL‐6) levels were measured, and HMGB1 immunohistochemistry was performed on biopsies taken before and after reperfusion. Plasma HMGB1 was undetectable before reperfusion, and levels in systemic circulation peaked after graft reperfusion. At portal declamping, HMGB1 levels were substantially higher in the caval effluent [188 (80‐371) ng/mL] than in portal venous blood [0 (0‐3) ng/mL, P < 0.001]. HMGB1 release from the graft continued thereafter. HMGB1 levels were not related to TNF‐α or IL‐6 levels. HMGB1 expression was up‐regulated in biopsies taken after reperfusion (P = 0.020), with intense hepatocyte and weak neutrophil staining. HMGB1 levels in hepatic venous blood correlated with graft steatosis (r = 0.497, P = 0.03) and peak postoperative alanine aminotransferase levels (r = 0.588, P = 0.008). Our results indicate that HMGB1 originates from the graft and is a marker of hepatocellular injury in human liver transplantation. Liver Transpl 14:1517–1525, 2008.

Immunosuppression After Liver Transplantation for Primary Sclerosing Cholangitis Influences Activity of Inflammatory Bowel Disease

BACKGROUND & AIMS Previous studies have shown conflicting results regarding the course of inflammatory bowel disease (IBD) after liver transplantation in patients with primary sclerosing cholangitis (PSC). We studied the progression of IBD in patients with PSC who have undergone liver transplantation. We also studied risk factors, including medical therapy, that could influence on IBD disease activity. METHODS In a longitudinal multicenter study, we analyzed data from the Nordic Liver Transplant Group on 439 patients with PSC who underwent liver transplantation from November 1984 through December 2006; 353 had IBD at the time of transplantation. We compared IBD activity before and after liver transplantation. Two hundred eighteen patients who had an intact colon and had undergone pretransplant and post-transplant colonoscopies were characterized further. RESULTS Macroscopic colonic inflammation was more frequent after liver transplantation than before liver transplantation (153 vs 124 patients; P < .001). The degree of inflammation decreased in 37 patients (17%), was unchanged in 93 patients (43%), and increased in 88 patients (40%) (P < .001). The rate of relapse after transplantation was higher than that before transplantation (P < .001), and overall clinical IBD activity also increased (P < .001). Young age at diagnosis of IBD and dual treatment with tacrolimus and mycophenolate mofetil were significant risk factors for increased IBD activity after transplantation, whereas combination treatment with cyclosporin A and azathioprine had protective effects. CONCLUSIONS Immunosuppression affects IBD activity after liver transplantation in patients with PSC; a shift from present standard maintenance treatment of tacrolimus and mycophenolate mofetil to cyclosporin A and azathioprine should be considered for these patients.

Liver transplantation in the Nordic countries – An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982–2013

Abstract Aim and background. The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013. Materials and methods. The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report. Results. Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004–2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively. Conclusion. The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).

Differences in long‐term survival among liver transplant recipients and the general population: A population‐based nordic study

Dramatic improvement in first‐year outcomes post‐liver transplantation (LT) has shifted attention to long‐term survival, where efforts are now needed to achieve improvement. Understanding the causes of premature death is a prerequisite for improving long‐term outcome. Overall and cause‐specific mortality of 3,299 Nordic LT patients (1985‐2009) having survived 1 year post‐LT were divided by expected rates in the general population, adjusted for age, sex, calendar date, and country to yield standardized mortality ratios (SMRs). Data came from the Nordic Liver‐Transplant Registry and WHO mortality‐indicator database. Stagnant patient survival rates >1 year post‐LT were 21% lower at 10 years than expected survival for the general population. Overall SMR for death before age 75 (premature mortality) was 5.8 (95% confidence interval [CI] 5.4‐6.3), with improvement from 1985‐1999 to 2000‐2010 in hepatitis C (HCV) (SMR change 23.1‐9.2), hepatocellular carcinoma (HCC) (SMR 38.4‐18.8), and primary sclerosing cholangitis (SMR 11.0‐4.2), and deterioration in alcoholic liver disease (8.3‐24.0) and acute liver failure (ALF) (5.9‐7.6). SMRs for cancer and liver disease (recurrent or transplant‐unrelated disease) were elevated in all indications except primary biliary cirrhosis (PBC). Absolute mortality rates underestimated the elevated premature mortality from infections (SMR 22‐693) and kidney disease (SMR 13‐45) across all indications, and from suicide in HCV and ALF. SMR for cardiovascular disease was significant only in PBC and alcoholic liver disease, owing to high mortality in the general population. Transplant‐specific events caused 16% of deaths. Conclusion: standardized premature mortality provided an improved picture of long‐term post‐LT outcome, showing improvement over time in some indications, not revealed by overall absolute mortality rates. Causes with high premature mortality (infections, cancer, kidney and liver disease, and suicide) merit increased attention in clinical patient follow‐up and future research. (Hepatology 2015;61:668‐677)

Gut intramucosal pH as an early indicator of effectiveness of therapy for hemorrhagic shock.

OBJECTIVE To determine the value of intramucosal pH for evaluating the effectiveness of treatment for hemorrhagic shock. DESIGN Randomized, controlled trial. SETTING University center, animal laboratory. SUBJECTS Eighteen piglets, weighing 17 to 23 kg. INTERVENTIONS Anesthetized animals were bled to a mean arterial pressure (MAP) of 40 to 50 mm Hg and a 70% reduction in cardiac output during a 1-hr period. This state was maintained for the next hour. The piglets were treated with crystalloid solution to restore cardiac output and MAP during the subsequent 80 mins of the experiment. Some animals were given vasoactive drugs during volume therapy to modulate splanchnic perfusion and increase the diversity of values of various variables. MEASUREMENTS AND MAIN RESULTS Systemic hemodynamic and oxygen transport variables were monitored. Tissue oxygen tensions were measured in the liver and abdominal subcutaneous tissue layer. Gut intramucosal pH (pHi) was determined, using a balloon tonometer. The animals were divided into responders (n=9) and nonresponders (n=9) according to whether pHi increased or decreased during resuscitation. Hemodynamic and oxygen transport variables improved in the group of responders. In the group of nonresponders, values decreased. Liver and subcutaneous oxygen tensions increased during the initial phase of resuscitation in both groups but decreased after 30 mins in the nonresponder group. CONCLUSIONS The change in pHi during the first hour of resuscitation could be used to divide animals treated uniformly from a hemodynamic point of view into two distinct groups with seemingly different outcome. The minimally invasive method could be of value for early evaluation of the results of treatment of hemorrhagic shock.

Effects of bicarbonate therapy on tissue oxygenation during resuscitation of hemorrhagic shock

We investigated the effects of clinically appropriate doses of NaHCO3 on tissue oxygenation when hemorrhagic shock was corrected with hydroxyethyl starch (hetastarch) in 12 piglets. Six animals received colloid only while six received colloid and bicarbonate. Both groups recovered rapidly hemodynamically, but conjunctival, subcutaneous, and liver tissue PO2 values returned to baseline more slowly after bicarbonate administration. In the NaHCO3 group, pulmonary artery wedge pressure and arterial bicarbonate concentration were higher during early resuscitation, and arterial plasma lactate remained higher than in the control group at the end of the follow-up period. The delayed increase in tissue PO2 values after bicarbonate infusion may be explained, at least partly, by decreased arterial blood oxygenation and a shift of the oxyhemoglobin curve to the left. NaHCO3 adjunct has no added beneficial effect on hemodynamics and may be harmful to tissue oxygenation in hemorrhagic shock resuscitated with hetastarch.

Peripheral and liver tissue oxygen tensions in hemorrhagic shock

ConclusionsReductions of both peripheral and portal venous Po2 values occur early during hemorrhage. The liver tissue Po2, though initially low, appears to be better defended, suggesting either redistribution of splanchnic blood flow or adaptation in hepatic oxygen demand. (Crit Care Med 1992; 20:1330–1334)

Enhanced recovery protocol after liver resection

Enhanced recovery protocols (ERPs) accelerate patient recovery and shorten hospital stay by optimization of perioperative care. However, experience with ERPs is still limited in liver surgery.

dopamine infusion during resuscitation of experimental hemorrhagic shock

Objective: To compare the effects of starting dopamine administration early or late on organ perfusion by measuring tissue oxygen tensions during standard volume resuscitation of hemorrhagic shock. Design: Randomized, control trial. Subjects: Thirteen piglets (mean weight, 19 kg). Interventions: The animals were bled to a state of hemorrhagic shock and resuscitated using crystalloid solution. Cardiac outputs and mean arterial pressures were measured as indicators of volume filling over a period of 80 mins. Dopamine was administered by infusion at 5 &mgr;g/kg/min from the start of volume correction (early‐dopamine group, n = 7) or after the volume deficit was corrected (late‐dopamine group, n = 6). Measurements and Main Results: Blood pressures and cardiac output were measured. Tissue oxygen tensions were continuously recorded in the liver, conjunctiva, and via subcutaneous and transcutaneous electrodes in the abdominal region. Mean arterial pressure decreased from 111 ± 5 (sem) to 44 ± 2 mm Hg with the induction of hemorrhagic shock. Cardiac output decreased by 78% during shock. During resuscitation, mean arterial pressure increased to near baseline values in both groups. Cardiac output recovered completely in the late‐dopamine group and almost completely in the early‐dopamine group. Liver oxygen tension increased to above baseline during resuscitation in the early‐dopamine group. Liver oxygen tension in the early‐dopamine group was significantly higher than in the late‐dopamine group. Similar changes were observed in subcutaneous and transcutaneous oxygen tensions, but not in conjunctival oxygen tensions. Conclusions: Starting dopamine administration early during volume resuscitation in a model of experimental hemorrhagic shock led to higher liver, subcutaneous, and transcutaneous tissue oxygen levels. This finding indicates enhanced tissue oxygen perfusion, especially in the liver. (Crit Care Med 1994; 22:151‐156)

Prognostic value of serum MMP-8, -9 and TIMP-1 in patients with hepatocellular carcinoma

Abstract Aim. Prediction of prognosis in hepatocellular carcinoma (HCC) is difficult. The aim of this study was to evaluate the prognostic value of serum MMP-8, -9, -13, and TIMP-1 in patients with HCC. Methods. Pre-treatment serum samples from 134 patients with HCC were retrospectively analyzed. The serum concentration of MMP-8 was analyzed with immunofluorometric assay (IFMA), and those of MMP-9, MMP-13, and TIMP-1 were determined by enzyme-linked immunosorbent assays (ELISA). Clinical data were retrieved from patient records and survival data obtained from Statistics Finland. Results. The overall cumulative disease-specific survival was 69% at 1 year, 50% at 2 years, and 33% at 5 years. Kaplan–Meier overall survival analysis showed that patients with low concentrations of serum MMP-8 or TIMP-1 had a statistically significantly better overall survival than patients with high concentrations of serum MMP-8 or TIMP-1 (P = 0.013 and P = 0.003). Interestingly, the overall survival in patients with high MMP-9/TIMP-1 ratio was statistically significantly better than in those patients with low MMP-9/TIMP-1 ratio (P = 0.004). Conclusion. Our results suggest that serum MMP-8, TIMP-1, and the ratio of MMP-9/TIMP-1 might be useful adjuncts as predictors of prognosis in patients with HCC.