Steven W.M. Olde Damink

Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure

Background. During orthotopic liver transplantation (OLT) for acute liver failure (ALF), some patients develop acute increases in intracranial pressure (ICP). The authors tested the hypothesis that increases in ICP during OLT for ALF can be prevented by moderate hypothermia. Methods. Sixteen patients with ALF undergoing OLT were studied. Depending on the measured ICP before OLT, the patients were divided into three groups as follows: group I (n=6), did not require treatment for increased ICP (ICP <15 mm Hg); group II (n=5), had episodes of increased ICP that were controlled by conventional treatment (group I and group II patients were maintained normothermic during OLT); and group III (n=5), had uncontrolled increased ICP before OLT for which they had been cooled and underwent OLT with the median core temperature of 33.4°C (92.1°F) (range, 31.9°–33.8°C [89.4°–92.8°F]) Results. There was a significant increase in ICP during the dissection and reperfusion phases in the patients in groups I and II (P =0.004 and P =0.006, respectively). Patients in group III had no significant increase in ICP during the OLT. The increase in ICP in groups I and II was associated with an increase in cerebral blood flow, which was not observed in group III. The increase in ICP was corrected during the anhepatic phase of the operation. There was no difference in the requirement of transfusions or incidence of postoperative infection between the groups. Conclusions. Moderate hypothermia is safe and successfully prevents increases in ICP during OLT for ALF.

Interorgan ammonia metabolism in liver failure

In the post-absorptive state, ammonia is produced in equal amounts in the small and large bowel. Small intestinal synthesis of ammonia is related to amino acid breakdown, whereas large bowel ammonia production is caused by bacterial breakdown of amino acids and urea. The contribution of the gut to the hyperammonemic state observed during liver failure is mainly due to portacaval shunting and not the result of changes in the metabolism of ammonia in the gut. Patients with liver disease have reduced urea synthesis capacity and reduced peri-venous glutamine synthesis capacity, resulting in reduced capacity to detoxify ammonia in the liver. The kidneys produce ammonia but adapt to liver failure in experimental portacaval shunting by reducing ammonia release into the systemic circulation. The kidneys have the ability to switch from net ammonia production to net ammonia excretion, which is beneficial for the hyperammonemic patient. Data in experimental animals suggest that the kidneys could have a major role in post-feeding and post-haemorrhagic hyperammonemia.During hyperammonemia, muscle takes up ammonia and plays a major role in (temporarily) detoxifying ammonia to glutamine. Net uptake of ammonia by the brain occurs in patients and experimental animals with acute and chronic liver failure. Concomitant release of glutamine has been demonstrated in experimental animals, together with large increases of the cerebral cortex ammonia and glutamine concentrations. In this review we will discuss interorgan trafficking of ammonia during acute and chronic liver failure. Interorgan glutamine metabolism is also briefly discussed, since glutamine synthesis from glutamate and ammonia is an important alternative pathway of ammonia detoxification. The main ammonia producing organs are the intestines and the kidneys, whereas the major ammonia consuming organs are the liver and the muscle.

Short chain fatty acids exchange across the gut and liver in humans measured at surgery.

BACKGROUND & AIMS Short chain fatty acids (SCFAs; acetate, propionate and butyrate) are important energy sources for colonocytes and are assumed to play a key role in gut health. Local effects of SCFAs have been investigated, but less is known about whole body metabolism of these SCFAs. The aim of the present study was to quantify the role of the gut and liver in interorgan exchange of SCFAs in humans in vivo. METHODS Twenty-two patients undergoing major upper abdominal surgery were studied. Blood was sampled from a radial artery, the portal and a hepatic vein. Portal, splanchnic and arterial blood flow was measured using intra-operative Duplex ultrasonography. SCFAs were measured on a liquid chromatography system combined with mass spectrometry. RESULTS SCFAs were released by the gut, 34.9 (9.1) micromol kg bodyweight(-1)h(-1). SCFAs uptake by the liver was significant for propionate and butyrate; -5.6 (1.3) and -3.8 (1.6) micromol kg bodyweight(-1)h(-1) (p=0.0002 and p=0.03) respectively and counterbalanced gut release. Liver uptake of acetate was not significant, -5.2 (6.6) micromol kg bodyweight(-1)h(-1) (p=0.434). Splanchnic (i.e., gut+liver) SCFAs release was significant for acetate and propionate, 17.3 (7.3) and 1.2 (0.4) micromol kg bodyweight(-1)h(-1) (p=0.027 and p=0.0038), respectively. Splanchnic release of butyrate was not significantly different from zero (1.9 (1.2) micromol kg bodyweight(-1)h(-1), p=0.129). BMI and previous colonic resection did not affect gut release of SCFAs. CONCLUSION This is the first in vivo study on the role of the gut and liver in SCFAs exchange in humans in vivo. It is shown that intestinal SCFAs release by the gut is equalled by hepatic uptake.

Interorgan ammonia metabolism in liver failure: the basis of current and future therapies.

Hepatic encephalopathy complicates the course of both acute and chronic liver disease and its treatment remains an unmet clinical need. Ammonia is thought to be central in its pathogenesis and remains an important target of current and future therapeutic approaches. In liver failure, the main detoxification pathway of ammonia metabolism is compromised leading to hyperammonaemia. In this situation, the other ammonia‐regulating pathways in multiple organs assume important significance. The present review focuses upon interorgan ammonia metabolism in health and disease describing the role of the key enzymes, glutamine synthase and glutaminase. Better understanding of these alternative pathways are leading to the development of new therapeutic approaches.

The effect of a multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study

OBJECTIVES This study was conducted to evaluate the added value of an enhanced recovery after surgery (ERAS) programme in laparoscopic liver resections for solid tumours. METHODS Patients undergoing laparoscopic liver resection between July 2005 and July 2008 were included. Indications for resections included presumed benign and malignant liver lesions. Primary outcome was total length of hospital stay (LOS). Secondary outcomes were functional recovery, complications, conversions, blood loss and duration of operation. RESULTS Thirteen patients were treated by laparoscopic liver resections in the ERAS programme in one centre (group 1). Their outcomes were compared with outcomes of 13 laparoscopic procedures performed either before the introduction of the ERAS programme during 2003-2005 in the same centre or during the same period in other centres using traditional care (group 2). Median total LOS was 5.0 days (range 3-10 days) in group 1 and 7.0 days (3-12 days) in group 2. This difference was not statistically significant. Functional recovery occurred 2 days earlier in group 1 (median 3.0 days [range 1-7 days] vs. median 5.0 days [range 2-8 days]; P < 0.044). There were no significant differences in complications, conversions or duration of operation. Blood loss was significantly less in the ERAS group (median 50 ml [range 50-200 ml] vs. median 250 ml [range 50-800 ml]; P < 0.002). CONCLUSIONS This exploratory, multicentre, fast-track laparoscopic liver resection study is the first such study conducted. Although small, the study suggests that a multimodal enhanced recovery programme in laparoscopic liver surgery is feasible, safe and may lead to accelerated functional recovery and reductions in LOS.

Pulmonary and Blood Stream Infections in Adult Living Donor and Cadaveric Liver Transplant Patients

Background. Infectious complications occur in approximately 50% of cadaveric liver transplant (CDLT) recipients. Living-donor liver transplantation (LDLT) is an established alternative to shorten the waiting time. Currently, the incidence of pulmonary infections after LDLT and the microbiologic causes are unknown. In the present cohort study, we compared the incidence and profiles of pulmonary and blood stream infections (BSI) between LDLT and CDLT recipients. We hypothesized a lower incidence in LDLT recipients. Methods. The clinical course of 55 LDLT recipients consecutively transplanted between January 2003 and December 2006 was analyzed. The 173 CDLT recipients who were transplanted in the same period served as a control group. Patients were treated in a single Intensive Care Unit, applying standardized postoperative care. Results. Mean model for end-stage liver disease score did not differ between LDLT and CDLT recipients (14.2 vs. 13.3). The overall incidence of pulmonary and BSI for both groups was 8% and 24%, respectively. Pulmonary infections were experienced by 18% of LDLT versus 5% of CDLT recipients (P=0.005) and BSI occurred in 33% of LDLT versus 21% of CDLT recipients (P=0.1). Conclusions. In contrast to our hypothesis, LDLT recipients experienced significantly more pulmonary infections and a trend toward increased higher incidence of BSI. These findings emphasize the need for future research on the causative agents and prevention of infection in LDLT recipients. The observation that patients with pulmonary infection had a significantly reduced 1-year survival rate underscores the importance of our observations.

Interorgan ammonia trafficking in liver disease

Patients with liver disease have reduced urea synthesis capacity resulting in reduced capacity to detoxify ammonia in the liver. The contribution of the gut to the hyperammonemic state observed during liver failure is mainly due to portacaval shunting and not the result of changes in the metabolism of ammonia in the gut. Small intestinal synthesis of ammonia is related to amino acid breakdown, predominantly glutamine, whereas large bowel ammonia production is caused by bacterial breakdown of amino acids and urea. The kidneys produce ammonia but adapt to liver failure in experimental portacaval shunting by reducing ammonia release into the systemic circulation. The kidneys have the ability to switch from net ammonia production to net ammonia excretion. Data from recent studies in patients with cirrhosis of the liver show that the kidneys have a major role in post upper gastrointestinal bleeding hyperammonemia. During hyperammonemia muscle takes up ammonia and plays a major role in (temporarily) detoxifying ammonia to glutamine. Net uptake of ammonia by the brain occurs in patients and experimental animals with acute and chronic liver failure. Insight will be given in recent developments on ammonia lowering therapies which are based on the information of interorgan ammonia trafficking.

The liver-first approach for synchronous colorectal liver metastasis: a 5-year single-centre experience

BACKGROUND For patients who present with synchronous colorectal carcinoma and colorectal liver metastasis (CRLM), a reversed treatment sequence in which the CRLM are resected before the primary carcinoma has been proposed (liver-first approach). The aim of the present study was to assess the feasibility and outcome of this approach for synchronous CRLM. METHODS Between 2005 and 2010, 22 patients were planned to undergo the liver-first approach. Feasibility and outcomes were prospectively evaluated. RESULTS Of the 22 patients planned to undergo the liver-first strategy, the approach was completed in 18 patients (81.8%). The main reason for treatment failure was disease progression. Patients who completed treatment and patients who deviated from the protocol had a similar location of the primary tumour, as well as comparable size, number and distribution of CRLM (all P > 0.05). Post-operative morbidity and mortality were 27.3% and 0% following liver resection and 44.4% and 5.6% after colorectal surgery, respectively. On an intention-to-treat-basis, overall 3-year survival was 41.1%. However, 37.5% of patients who completed the treatment had developed recurrent disease at the time of the last follow-up. CONCLUSIONS The liver-first approach is feasible in approximately four-fifths of patients and can be performed with peri-operative mortality and morbidity similar to the traditional treatment paradigm. Patients treated with this novel strategy derive a considerable overall-survival-benefit, although disease-recurrence-rates remain relatively high, necessitating a multidisciplinary approach.

Loss of skeletal muscle during neoadjuvant chemotherapy is related to decreased survival in ovarian cancer patients

Malnutrition, weight loss, and muscle wasting (sarcopenia) are common among women with advanced ovarian cancer and have been associated with adverse clinical outcomes and survival. Our objective is to investigate overall survival (OS) related to changes in skeletal muscle (SM) for patients with advanced ovarian cancer treated with neoadjuvant chemotherapy and interval debulking.

Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation

Non‐alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation. The transition from steatosis towards NASH represents a key step in pathogenesis, as it will set the stage for further severe liver damage. Under normal conditions, lipoproteins that are endocytosed by Kupffer cells (KCs) are easily transferred from the lysosomes into the cytoplasm. Oxidized LDL (oxLDL) that is taken up by the macrophages in vitro is trapped within the lysosomes, while acetylated LDL (acLDL) is leading to normal lysosomal hydrolysis, resulting in cytoplasmic storage. We have recently demonstrated that hepatic inflammation is correlated with lysosomal trapping of lipids. So far, a link between lysosomal trapping of oxLDL and inflammation was not established. We hypothesized that lysosomal trapping of oxLDL in KCs will lead to hepatic inflammation.