Vincent B. Nieuwenhuijs

Hepatic ischemia-reperfusion injury : roles of Ca2+ and other intracellular mediators of impaired bile flow and hepatocyte damage

Liver resection and liver transplantation have been successful in the treatment of liver tumors and end-stage liver disease. This success has led to an expansion in the pool of patients potentially treatable by liver surgery and, in the case of transplantation, to a shortage of liver donors. At present, there are significant numbers of potential candidates for liver resection and liver donation who have fatty livers, are aged, or have livers damaged by chemotherapy. All of these are at high risk for ischemic reperfusion (IR) injury. The aims of this review are to assess current knowledge of the clinical effectiveness of ischemic preconditioning and intermittent ischemia in reducing IR damage in liver surgery; to evaluate the use of bile flow as a sensitive indicator of IR liver damage; and to analyze the molecular mechanisms, especially intracellular Ca2 +, involved in IR injury and ischemic preconditioning. It is concluded that bile flow is a sensitive indicator of IR injury. Together with reactive oxygen species (ROS) and other extracellular and intracellular signaling molecules, intracellular Ca2 + in hepatocytes plays a key role in the normal regulation of bile flow and in IR-induced injury and cell death. Ischemic preconditioning is an effective strategy to reduce IR injury but there is considerable scope for improvement, especially in patients with fatty and aged livers. The development of effective new strategies to reduce IR injury will depend on improved understanding of the molecular mechanisms involved, especially by gaining a better perspective of the relative importance of the various intrahepatocyte signaling pathways involved.

Ischemic Preconditioning and Intermittent Ischemia Preserve Bile Flow in a Rat Model of Ischemia Reperfusion Injury

Ischemia and reperfusion (IR) injury of the liver is associated with impaired bile secretion, but the effects of ischemic preconditioning (IPC) and intermittent ischemia (INT) on bile flow are unknown. A rat model of segmental (60%–70%) hepatic ischemia and reperfusion was employed to test the effects of IPC and INT on bile flow. Continuous clamping for 45xa0min (CC) substantially reduced bile flow, and this did not recover after 60xa0min of reperfusion. IPC and INT caused a significant recovery of bile flow. The elevation in plasma liver marker enzymes induced by CC was not reduced by IPC and INT. Light microscopy showed mild hepatocyte damage in all groups. In the CC group, the amount of F-actin localized around the bile canaliculi in the ischemic lobes was less than that in the nonischemic lobes, but this difference was not observed in the IPC and INT groups. It is concluded that IPC and INT substantially alleviate the decrease in bile flow induced by ischemia. Bile flow may be useful in the assessment of IR injury.

Intermittent Ischemia but Not Ischemic Preconditioning Is Effective in Restoring Bile Flow After Ischemia Reperfusion Injury in the Livers of Aged Rats

BACKGROUND/AIMSnIschemic preconditioning (IPC) and intermittent ischemia (INT) reduce liver injury following ischemia reperfusion in liver resections. Aged livers are at higher risk for ischemia reperfusion injury, but little is known of the effectiveness of IPC and INT in aged livers. The aim of this study was to investigate the effects of IPC and INT on ischemia reperfusion injury in aged livers.nnnMETHODSnA rat model of segmental hepatic ischemia (45 min) and reperfusion (60 min) was used. Bile flow, as an indicator of early hepatocyte damage and dynamic liver function, plasma concentrations of bilirubin, liver marker enzymes, and liver histology were assessed.nnnRESULTSnIn young rats (8-13 weeks), IPC regimes of 10 min clamping and 10 min reperfusion, and 5 min clamping and 30 min reperfusion, restored bile flow to 23 and 42%, respectively, of the initial value, compared to 14 and 88% for continuous clamping and controls, respectively. An INT regime of three cycles of alternating 15 min perfusion and 15 min clamping gave a substantially greater (70%) restoration of bile flow. In aged rats (20-24 months), the IPC regimes did not give any restoration of bile flow. By contrast, the INT regime restored bile flow to 68%. Plasma bilirubin concentrations were lowest in the INT groups, whereas alanine transaminase concentrations for the IPC and INT groups compared with the continuous clamping groups showed no significant differences.nnnCONCLUSIONSnIn young rats, INT is more effective than IPC in restoring the immediate consequences of IP-induced damage to hepatocytes and liver function after ischemia-reperfusion. In aged rats INT, but not IPC, reverses hepatocyte damage and restores liver function. INT may promote better hepatocyte and liver function than IPC following the surgical resection of aged livers.

Increased expression of peroxiredoxin 1 and identification of a novel lipid-metabolizing enzyme in the early phase of liver ischemia reperfusion injury

Warm ischemia reperfusion (IR) injury of the liver is associated with changes in the expression and/or post‐translational modification of numerous proteins. Only a few of these have been identified. We used 2‐D DIGE to identify cytosolic proteins altered in the early stage of IR in an established rat model of segmental hepatic ischemia. Proteins in 18 abundant spots altered by IR were identified by LC‐MS/MS and Western blot. Many identified proteins were enzymes involved in glucose and lipid metabolism. Isoamyl acetate‐hydrolysing esterase 1 homolog, not previously characterized in liver, was also identified. A threefold increase in peroxiredoxin 1 (Prx1) and its oxidized forms was observed as was an increase in Prx1 mRNA. Peroxiredoxins and their overoxidation have previously been associated with IR. In contrast to other studies, we did not detect typical overoxidation of Prx1 on the peroxidatic cysteine (Cys52). Instead, we identified novel overoxidation of the resolving cysteine (Cys173) residue by LC‐MS/MS. Our results show that a rapid increase in Prx1 expression is associated with the early phase of IR of the liver, likely contributing to mechanisms that protect the liver against IR damage. Additionally, we have revealed a potential role in liver for a novel lipid‐metabolizing enzyme.

Intermittent ischaemia maintains function after ischaemia reperfusion in steatotic livers

BACKGROUNDnIschaemic preconditioning (IPC) and intermittent ischaemia (INT) reduce liver injury after ischaemia reperfusion (IR). Steatotic livers are at a higher risk of IR injury, but the protection offered by IPC and INT is not well understood. The aim of the present study was to determine the effectiveness of IPC and INT in maintaining liver function in steatotic livers.nnnMATERIAL AND METHODSnA model of segmental hepatic ischaemia (45 min) and reperfusion (60 min) was employed using lean and obese Zucker rats. Bile flow recovery was measured to assess dynamic liver function, hepatocyte fat content quantified and blood electrolytes, metabolites and bile calcium measured to assess liver and whole body physiology. Liver marker enzymes and light and electron microscopy were employed to assess hepatocyte injury.nnnRESULTSnIPC was not effective in promoting bile flow recovery after IR in either lean or steatotic livers, whereas INT promoted good bile flow recovery in steatotic as well as lean livers. However, the bile flow recovery in steatotic livers was less than that in lean livers. In steatotic livers, ischaemia led to a rapid and substantial decrease in fat content. Steatotic livers were more susceptible to IR injury than lean livers, as indicated by increased blood ALT concentrations and major histological injury.nnnCONCLUSIONnINT is more effective than IPC in restoring liver function in the acute phase of IR in steatotic livers. In obese patients, INT may be useful in promoting better liver function after IR after liver resection.

Measuring Outcomes of Laparoscopic Anti-reflux Surgery: Quality of Life Versus Symptom Scores?

IntroductionOutcome following fundoplication for gastroesophageal reflux can be measured using objective tests, symptom scores and quality of life (QoL) measures. Which is best and how these assessments correlate is uncertain. To determine the utility of assessment measures we compared a general QoL measure (SF-36) and a disease-specific measure (GERD-hr-QoL) with symptom and satisfaction scores in individuals following fundoplication.Methods329 individuals underwent fundoplication between 2000 and 2015 in 2 centres in Australia and the Netherlands. Patients were assessed before and 3, 12 and 24xa0months after surgery using 10-point Likert scales to assess heartburn and satisfaction, the SF-36 questionnaire and the GERD-hr-QoL questionnaire. SF-36 scores were converted into component scores: Physical Component Scale (PCS) score and Mental Component Scale (MCS) score. Correlations between QoL measures and clinical outcomes were determined.ResultsSurgery relieved heartburn (7.0 vs. 0.0 median, Pxa0<xa00.001) and patients were highly satisfied with the outcome (median 9.0). PCS and MCS scores improved after surgery (PCS 40.9 vs. 46.0, Pxa0<xa00.001; MCS 47.6 vs. 50.3, Pxa0=xa00.027). GERD-hr-QoL scores also improved after surgery (15.7 vs. 3.7, Pxa0<xa00.001). Correlations between PCS and MCS scores versus heartburn and satisfaction scores were generally weak or absent. However, correlations between GERD-hr-QoL versus heartburn and satisfaction scores were moderate to strong.ConclusionDespite improvements in scores, the SF-36 correlated poorly with clinical outcome measures, and its use to measure outcome following fundoplication is questioned. However, the GERD-hr-QoL correlated well with the symptom scores, suggesting this disease-specific QoL measure is a better tool for assessing anti-reflux surgery outcome.

LIVER TRANSPLANTATION: A SMALL-VOLUME UNIT EXPERIENCE

Background:u2003 Results of liver transplantation have improved significantly over the last three decades. Hospital volume has been cited as an important outcome factor. The South Australian (SA) programme commenced in 1992 as the fourth centre in Australia.

Rapamycin Induces Heme Oxygenase-1 in Liver but Inhibits Bile Flow Recovery after Ischemia

BACKGROUND/AIMSnRapamycin, which is employed in the management of patients undergoing liver surgery, induces the synthesis of heme oxygenase-1 (HO-1) in some non-liver cell types. The aim was to investigate whether rapamycin can induce HO-1 expression in the liver, and to test the effects of rapamycin on liver function in the early phase of ischemia reperfusion (IR) injury.nnnMETHODSnIsolated rat hepatocytes and a rat model of segmental hepatic ischemia and reperfusion were employed. Bile flow was measured gravimetrically or by using indocyanine green. mRNA and protein (by quantitative PCR and Western blot, respectively) and blood concentrations of rapamycin, bilirubin, and liver marker enzymes were measured.nnnRESULTSnIn isolated hepatocytes, rapamycin induced a 6-fold increase in HO-1, comparable to that induced by cobalt proporphyrin (CoPP), and a 2-fold increase in peroxiredoxin-1. Pretreatment of rats with rapamycin resulted in a small increase in liver HO-1 expression, a 20% inhibition of the basal rate of bile flow, and a 50% inhibition in the rate of bile flow recovery after ischemia. CoPP increased basal bile flow by 20% and inhibited bile flow recovery by 50%. These effects were associated with small increases in the blood concentrations of bilirubin and liver marker enzymes.nnnCONCLUSIONSnRapamycin, through HO-1 induction, has the potential to protect the liver against damage in the late phase of IR. The inhibition by rapamycin of bile flow indicates that its actions on liver function in the acute phase of IR injury are complex.

Surgical antisepsis and the risk of operating theatre fires.

Matthias Maiwald, Chris J. M. Farmer, David G. Lance, Vincent B. Nieuwenhuijs, Christopher H. Heath, David I. Watson, David L. Gordon

Caecal Herniation through the Foramen of Winslow

Internal hernia is the protrusion of an abdominal viscus through the peritoneum or mesentery into a compartment within the abdominal cavity. We present a case of internal herniation through the foramen of Winslow that was identified by CT imaging. It was treated with reduction at laparotomy and subsequent right hemicolectomy. SUMMARY Internal hernia refers to the protrusion of an abdominal viscus through the peritoneum or mesentery into a compartment within the abdominal cavity and represents an uncommon cause of bowel obstruction. Six main types of internal herniation have been described, which are paraduodenal, foramen of Winslow, transmesenteric, paracaecal, intersigmoid and paravesical. Of these, protrusion through the foramen of Winslow is rare and accounts only for approximately 8% of all internal herniae. Various organs have hitherto been found to herniate through this foramen. Here, we report a case of caecal herniation that was only diagnosed by a CT scan. CLINICAL PRESENTATION A 57-year-old male presented with a 1-day history of sudden onset epigastric and chest pain, associated with nausea, coffee ground vomiting and rectal bleeding. On systemic enquiry of the gastrointestinal system, there was no history of abdominal distension and the patient reported bowel opening the day prior to admission. He had no past history of abdominal surgery but suffered from Type 2 diabetes mellitus and learning difficulties. Clinical examination revealed mild epigastric tenderness in the absence of guarding and rigidity, but was accompanied by reduced bowel sounds, with no evidence of inguinal or femoral herniation. On admission, he was apyrexial and results of blood test showed an increased white cell count (16.1, normal range 4–11 10 l), amylase (279, normal range 30–123U l) and alanine transaminase (60, normal range 9–55U l), as well as deranged renal function tests (creatinine, 151, normal range 36–107mmol l; urea, 15.5, normal range 2.5–7.8mmol l). Erect chest and abdominal radiography demonstrated gas collection under the hemidiaphragm within a bowel loop but no free air, as well as a distended stomach. The patient was admitted under the medical team with a differential diagnosis of acute coronary syndrome, but his electrocardiogram and troponin were unremarkable. A surgical opinion was therefore requested. An urgent CT scan of the abdomen and pelvis demonstrated large pockets of gas and faeces in the left hypochondrium adjacent to the stomach. This was suggestive of an abnormally lying caecum, secondary to either internal herniation or a volvulus. There was no evidence of free gas in the abdomen. Figure 1 shows a coronal section of the CT scan. Here, the stomach (S) is lying below the left hemidiaphragm with the caecum (C) below it and passing through the foramen of Winslow. An axial view is shown in Figure 2, where the caecum is located behind the stomach. The patient underwent urgent laparotomy that confirmed an internal hernia of the caecum through the foramen of Winslow, lying behind the stomach in the lesser sac causing small bowel obstruction. The caecum showed evidence of ischaemia and necrosis, but there was no abdominal contamination (Figure 3). During surgery, after gaining access via the lesser sac, the caecum was decompressed and subsequently reduced through the foramen. A right hemicolectomy was performed with a side-to-side stapled anastomosis. Postoperatively, the patient was transferred to the high dependency unit, went on to have an uneventful recovery and was discharged home a week later. DISCUSSION Internal hernia refers to the protrusion of an abdominal viscus through the peritoneum or mesentery into a compartment within the abdominal cavity. It is an uncommon cause of small bowel obstruction, accounting for around 5% of all cases. Timely diagnosis is crucial because BJR|case reports http://dx.doi.org/10.1259/bjrcr.20150330