Vincent E. de Meijer

Abstract: Aim: While low grade inflammation persists in both visceral fat and hepatic tissue in obesity, these changes often result in progressive disease and fibrosis only in the liver and not in adipose tissue. We hypothesized that a tissue-specific difference in obesity-induced inflammatory cell infiltrate may be responsible for such organ difference in susceptibility to fibrosis. Methods: Mice were fed either standard chow or a high fat diet over 19 weeks. Hepatic steatosis was assessed by histology and quantified via magnetic resonance spectroscopy. Immunohistochemistry staining for macrophage subsets and quantitative reverse transcription-polymerase chain reaction for matrix metalloproteinase (MMP)- and fibrosis-related gene expression was performed in paired livers and visceral (epididymal) fat pads at early (9 weeks) and advanced (19 weeks) stages of progressive diet-induced obesity. Results: Up to 19 weeks of high fat feeding led to the development of obesity and hepatic steatosis, as well as increased gene expression of Mmp12, Mmp13 and Timp1 in predominantly adipose tissue, and to a lesser extent of liver tissue. In contrast to visceral fat, cell counts for macrophages as well as profibrogenic gene signaling in liver tissue during development of diet-induced obesity remained largely unchanged. Conclusions: Development of diet-induced obesity in the mouse increased inflammatory macrophages counts in adipose tissue rather than the liver. This was associated with greater increases in MMP expression in adipose tissue compared with liver. We propose that attenuated hepatic MMP expression in livers and adipose tissue of obese mice shifts the balance of fibrogenesis/fibrolysis and predispose the liver to development of fibrosis.

Abstract: PURPOSE: This study compares postoperative markers of liver injury in patients receiving intravenous fish oil (IFO) with parenteral nutrition (PN)-associated cholestasis (PNAC) to patients with resolved PNAC. METHODS: A retrospective review of all cholestatic-IFO patients undergoing abdominal laparotomy between March 1, 2007, and July 1, 2009, led to inclusion of 23 patients who collectively underwent 27 abdominal operations (13 pre-PNAC resolution and 14 post-PNAC resolution). Direct bilirubin (DB), total bilirubin, and alanine aminotransferase levels were examined over time in relation to operations. The time to resume presurgical trend of decreasing DB was calculated. RESULTS: Sixty-nine percent (9/13) of pre-PNAC resolution procedures were associated with postoperative increase in DB compared with 7% (1/14) of post-PNAC resolution procedures associated with a recurrence of cholestasis (P = .02; odds ratio, 29.3; 95% confidence interval, 2.79-306.8). The median time to return to the preoperative downward trend of DB was 21 days. CONCLUSIONS: Operations before PNAC resolution may be associated with an increased postoperative DB, possibly reflecting an exacerbation of liver injury. Operations post-PNAC resolution on IFO had a comparatively low incidence of postoperative cholestasis recurrence. Excepting clinical indication otherwise, it may be advisable to delay surgical intervention in the setting of PNAC in certain cases.

Abstract: BACKGROUND: Plant-based intravenous lipid emulsions have been shown to contribute to parenteral nutrition-associated liver disease (PNALD). There is mounting evidence that fish oil-based emulsions may prevent this liver injury. This study compares 5 emulsions with different fat compositions and their effect on hepatic steatosis, one of the first hits in PNALD. METHODS: C57BL/6J mice were placed on a fat-free diet and randomized into 5 equal groups. Each group received one of the commercially available intravenous lipid emulsions (Intralipid [Baxter/Fresenius Kabi, Deerfield, Ill], Liposyn II [Hospira Inc, Lake Forest, Ill], ClinOleic [Baxter/Clintec Parenteral SA, Cedex, France], SMOFlipid [Fresenius Kabi, Bad Homburg, Germany], or Omegaven [Fresenius Kabi Deutschland GmbH]) or normal saline. Liver enzymes, degree of steatosis, and fatty acid compositions were analyzed after 19 days. RESULTS: Intralipid, Liposyn II, ClinOleic, and SMOFlipid groups all demonstrated moderate steatosis with hepatic fat contents of 17.4%, 21.9%, 22.5%, and 12.6%, respectively. Omegaven mice, however, had normal livers. Saline control mice developed biochemical evidence of essential fatty acid deficiency (EFAD). Lipid supplementation with Intralipid, Liposyn II, and Omegaven prevented the onset of biochemical EFAD, whereas administration of ClinOleic and SMOFlipid did not. CONCLUSION: The fish oil-based lipid emulsion Omegaven prevented hepatic steatosis and EFAD in this murine model. omega-3 fatty acids may be efficacious in preventing PNALD and should be explored in the development of novel lipid emulsions.

Abstract: Objectives: Essential fatty acids are important for growth, development, and physiologic function. alpha-Linolenic acid and linoleic acid are the precursors of docosahexaenoic and arachidonic acid, respectively, and have traditionally been considered the essential fatty acids. However, the authors hypothesized that docosahexaenoic acid and arachidonic acid can function as the essential fatty acids. METHODS: Using a murine model of essential fatty acid deficiency and consequent hepatic steatosis, the authors provided mice with varying amounts of docosahexaenoic and arachidonic acids to determine whether exclusive supplementation of docosahexaenoic and arachidonic acids could prevent essential fatty acid deficiency and inhibit or attenuate hepatic steatosis. RESULTS: Mice supplemented with docosahexaenoic and arachidonic acids at 2.1% or 4.2% of their calories for 19 days had normal liver histology and no biochemical evidence of essential fatty acid deficiency, which persisted when observed after 9 weeks. Conclusion: Supplementation of sufficient amounts of docosahexaenoic and arachidonic acids alone without alpha-linolenic and linoleic acids meets essential fatty acid requirements and prevents hepatic steatosis in a murine model. (JPEN J Parenter Enteral Nutr. XXXX;xx:xx-xx).

Abstract: BACKGROUND: Hepatic steatosis is an established risk factor for complications following major hepatic resection. Pharmacological options to reverse steatosis prior to surgery, however, are lacking. We hypothesized that treatment with the pharmacologic tumor necrosis factor-alpha converting enzyme (TACE)-inhibitor Marimastat would reverse established steatosis, leading to improved outcome following hepatectomy. METHODOLOGY/PRINCIPAL FINDINGS: C57BL/6 male mice were fed a high fat diet for 9 weeks to establish obesity, hepatic steatosis and insulin resistance, and were administered either Marimastat or vehicle for an additional 2 or 4 weeks. Leptin deficient, hyperinsulinemic ob/ob mice were treated with Marimastat for 4 weeks. Hepatic steatosis was quantified by magnetic resonance spectroscopy and confirmed by histology. After two weeks, Marimastat-treated animals significantly improved surrogate markers for insulin sensitivity and liver histology, and experienced a 66% decrease in steatosis (P = 0.010). These findings were confirmed in ob/ob mice. Transcripts related to fatty acid synthesis were significantly downregulated in Marimastat-treated animals. Following pre-treatment with Marimastat or vehicle for two weeks, high fat fed C57BL/6 mice were subjected to two-thirds hepatectomy. Post-operative liver injury as quantified by serum aspartate aminotransferase levels and alanine aminotransferase levels was significantly decreased by 57% (P = 0.020) and 44% (P = 0.032) respectively, compared to controls. CONCLUSION/SIGNIFICANCE: Treatment with the TACE-inhibitor Marimastat improved surrogate markers for insulin sensitivity and reversed steatosis in mouse models of diet-induced obesity and leptin deficiency, thereby attenuating post-operative injury following hepatectomy. This may suggest a potential therapeutic role in patients with fatty liver disease; especially those who need to undergo hepatic resection.

Abstract: BACKGROUND: Postoperative abdominal adhesions are a major cause of morbidity and mortality. We previously demonstrated the inhibitory effect of sunitinib, a receptor tyrosine kinase inhibitor, on adhesion formation in a murine model, and now investigate its effects in a rabbit model. METHODS: Forty New Zealand White rabbits underwent a standard adhesion procedure. Preoperatively, animals were randomized to treatment with sunitinib or saline (control). Animals were treated with a total of 11 daily doses, 1 preoperative and 10 postoperative. One group of 20 animals (group 1) was humanely killed on postoperative day 10, and the other (group 2) on postoperative day 30. After killing, adhesions were scored and abdominal wounds were collected for tensile strength and microvessel density measurements. RESULTS: Sunitinib-treated animals in group 1 had a mean tenacity score of 1.67 +/- 0.29 compared with 3.60 +/- 0.16 in control animals (P < .01). Similarly, the mean tenacity scores for sunitinib-treated and control animals in group 2 were 0.20 +/- 0.20 and 2.70 +/- 0.37, respectively (P < .01). The mean uterine involvement scores for sunitinib-treated and control animals in group 1 were 1.44 +/- 0.29 and 3.70 +/- 0.15, respectively (P < .01), and in group 2 were 0.10 +/- 0.10 and 2.70 +/- 0.45, respectively (P < .01). There were no differences in ultimate or modular wound tensile strength between sunitinib-treated and control animals. CONCLUSION: Sunitinib significantly reduces postoperative adhesions in a rabbit model. This therapy may improve postoperative adhesion-related morbidity and mortality.

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Abstract: BACKGROUND: Total parenteral nutrition (PN), including fat administered as a soybean oil-based lipid emulsion (SOLE), is a life-saving therapy but may be complicated by PN-induced cholestasis and dyslipidemia. A fish-oil-based lipid emulsion (FOLE) as a component of PN can reverse PN-cholestasis and has been shown to improve lipid profiles. OBJECTIVE: The objective was to describe changes in the fatty acid and lipid profiles of children with PN-cholestasis who were treated with a FOLE. DESIGN: Lipid and fatty acid profiles of 79 pediatric patients who developed PN-cholestasis while receiving standard PN with a SOLE were examined before and after the switch to a FOLE. All patients received PN with the FOLE at a dose of 1 g . kg(-1) . d(-1) for >/=1 mo. RESULTS: The median (interquartile range) age at the start of the FOLE treatment was 91 (56-188) d. After a median (interquartile range) of 18.3 (9.4-41.4) wk of receiving the FOLE, the subjects' median total and direct bilirubin improved from 7.9 and 5.4 mg/dL to 0.5 and 0.2 mg/dL, respectively (P < 0.0001). Serum triglyceride, total cholesterol, LDL, and VLDL concentrations significantly decreased by 51.7%, 17.4%, 23.7%, and 47.9%, respectively. CONCLUSIONS: The switch from a SOLE to a FOLE in PN-dependent children with cholestasis and dyslipidemia was associated with a dramatic improvement in serum triglyceride and VLDL concentrations, a significant increase in serum omega-3 (n-3) fatty acids (EPA and DHA), and a decrease in serum omega-6 fatty acids (arachidonic acid). A FOLE may be the preferred lipid emulsion in patients with PN-cholestasis, dyslipidemia, or both. This trial is registered at clinicaltrials.gov as NCT00910104.

Abstract: Children with intestinal failure (IF) suffer from insufficient intestinal length or function, making them dependent on parenteral nutrition (PN) for growth and survival. PN and its components are associated with many complications ranging from simple electrolyte abnormalities to life-threatening PN-associated liver disease, which is also called intestinal failure-associated liver disease (IFALD). From a nutrition perspective, the ultimate goal is to provide adequate caloric requirements and make the transition from PN to full enteral nutrition (EN) successful. Upon review of the literature, we have summarized the most effective and innovative PN and EN therapies for this patient population. Antibiotic-coated catheters and antibiotic or ethanol locks can be implemented, as they appear effective in reducing catheter-related infection and thus further reduce the risk of IFALD. Lipid emulsions should be given judiciously. The use of an omega-3 fatty acid-based formulation should be considered in patients who develop IFALD. Trophic feeding is important for intestinal adaptation, and EN should be initiated early to help wean patients from PN. Long-term management of children with IF continues to be an emerging field. We have entered uncharted territory as more children survive complications of IF and IFALD. Careful monitoring and individualized management to ensure maintenance of growth while avoiding complications are the keys to successful patient outcomes.

Abstract: BACKGROUND: Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily by matrix metalloproteinases (MMPs). The effect of pharmacological MMP inhibition on fibrogenesis, however, is largely unexplored. Inflammation is considered a prerequisite and important co-contributor to fibrosis and is, in part, mediated by tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). We hypothesized that treatment with a broad-spectrum MMP and TACE-inhibitor (Marimastat) would ameliorate injury and inflammation, leading to decreased fibrogenesis during repeated hepatotoxin-induced liver injury. METHODOLOGY/PRINCIPAL FINDINGS: Liver fibrosis was induced in mice by repeated carbon tetrachloride (CCl4) administration, during which the mice received either Marimastat or vehicle twice daily. A single dose of CCl4 was administered to investigate acute liver injury in mice pretreated with Marimastat, mice deficient in Mmp9, or mice deficient in both TNF-alpha receptors. Liver injury was quantified by alanine aminotransferase (ALT) levels and confirmed by histology. Hepatic collagen was determined as hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated liver injury and inflammation but a 25% increase in collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while MMP expression and activity analysis revealed efficient pharmacologic MMP-inhibition and decreased fibrolysis following Marimastat treatment. Marimastat pre-treatment significantly attenuated liver injury following acute CCl4-administration, whereas Mmp9 deficient animals demonstrated no protection. Mice deficient in both TNF-alpha receptors exhibited an 80% reduction of serum ALT, confirming the hepatoprotective effects of Marimastat via the TNF-signaling pathway. CONCLUSIONS/SIGNIFICANCE: Inhibition of MMP and TACE activity with Marimastat during chronic CCl4 administration counterbalanced any beneficial anti-inflammatory effect, resulting in a positive balance of collagen deposition. Since effective inhibition of MMPs accelerates fibrosis progression, MMP inhibitors should be used with caution in patients with chronic liver diseases.

Abstract: BACKGROUND: Parenteral nutrition (PN) is a life-saving therapy but has been associated with dyslipidemia. Because fish oil has been shown to have positive effects on lipid profiles, the authors hypothesize that a parenteral fish oil lipid emulsion will improve lipid profiles in children who are PN dependent. METHODS: The authors examined the lipid profiles of a unique cohort of 10 children who were exclusively administered a fish oil-based lipid emulsion while on PN for a median duration of 14 weeks. Longitudinal data analysis with a generalized estimating equations approach was used to determine the sterol and bilirubin levels based on duration of the fish oil-based lipid emulsion. RESULTS: After 14 weeks of fish oil monotherapy, children had a 24% increase in high-density lipoprotein. Compared to baseline, serum low-density lipoprotein, very low-density lipoprotein, total cholesterol, and triglyceride levels all significantly decreased by 22%, 41%, 17%, and 46%, respectively. Eight children had their bilirubin improved with a decreased direct bilirubin from 6.9 mg/dL (range, 4.4-10.7) at baseline to 2.3 mg/dL (range, 1.3-4.0) after 14 weeks, and a decrease in total bilirubin from 8.7 mg/dL (range, 5.5-13.7) to 3.8 mg/dL (range, 2.2-6.5). CONCLUSION: A fish oil-based lipid emulsion used as monotherapy in children who exclusively depended on PN for survival was associated with significant improvement in all major lipid panels as well as improvement of hyperbilirubinemia. Parenteral fish oil may be the preferred lipid source in children with dyslipidemia.

Abstract: Interest in pharmacological intervention to combat metabolic syndrome and its complications is increasing as the prevalence of obesity is reaching epidemic proportions. The potential efficacy of drugs is often tested in animal models; however, the method of drug delivery is frequently overlooked and may act as a confounder due to stress. We hypothesized that long-term orogastric gavage would negatively influence the development of hepatic steatosis and the metabolic syndrome in a murine model of diet-induced obesity. C57BL/6J male mice were fed a high fat diet and were gavaged with a vehicle once or twice daily for 9 weeks. A group without orogastric gavaging served as control. A similar experiment was performed using leptin deficient ob/ob mice that were fed a standard diet for 4 weeks. Food intake was monitored, insulin resistance determined, and steatosis was assessed by histology and quantified via magnetic resonance spectroscopy. After 9 weeks, control C57BL/6J mice exhibited significantly more weight gain, insulin resistance and hepatic steatosis, compared to mice that were gavaged daily, or twice daily. This effect was likely due to decreased food consumption associated with gavage-induced stress. In contrast, the phenotype of leptin deficient ob/ob mice was not affected by orogastric gavage. Therefore, we concluded that orogastric gavage may lead to increased stress, thereby affecting food intake and the development of diet-induced obesity in a murine model. The effects of what may seem to be trivial laboratory routines, such as orogastric gavage, should be taken into account when designing animal studies for drug development.

Abstract: BACKGROUND: Parenteral nutrition (PN) is a life-saving therapy but has been associated with dyslipidemia. Because fish oil has been shown to have positive effects on lipid profiles, the authors hypothesize that a parenteral fish oil lipid emulsion will improve lipid profiles in children who are PN dependent. METHODS: The authors examined the lipid profiles of a unique cohort of 10 children who were exclusively administered a fish oil-based lipid emulsion while on PN for a median duration of 14 weeks. Longitudinal data analysis with a generalized estimating equations approach was used to determine the sterol and bilirubin levels based on duration of the fish oil-based lipid emulsion. RESULTS: After 14 weeks of fish oil monotherapy, children had a 24% increase in high-density lipoprotein. Compared to baseline, serum low-density lipoprotein, very low-density lipoprotein, total cholesterol, and triglyceride levels all significantly decreased by 22%, 41%, 17%, and 46%, respectively. Eight children had their bilirubin improved with a decreased direct bilirubin from 6.9 mg/dL (range, 4.4-10.7) at baseline to 2.3 mg/dL (range, 1.3-4.0) after 14 weeks, and a decrease in total bilirubin from 8.7 mg/dL (range, 5.5-13.7) to 3.8 mg/dL (range, 2.2-6.5). CONCLUSION: A fish oil-based lipid emulsion used as monotherapy in children who exclusively depended on PN for survival was associated with significant improvement in all major lipid panels as well as improvement of hyperbilirubinemia. Parenteral fish oil may be the preferred lipid source in children with dyslipidemia.

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Abstract: OBJECTIVE: The use of fish oil-based emulsions as the sole source of fat for patients receiving parenteral nutrition (PN) has raised concerns for the development of essential fatty acid deficiency (EFAD), hindering its adoption into clinical practice. The purpose of the present study was to examine fatty acid profiles of patients receiving no enteral energy, while completely dependent on PN and an intravenous fish oil-based lipid emulsion, for onset of EFAD and maintenance of growth. PATIENTS AND METHODS: Prospectively collected data from 10 patients were reviewed for evidence of EFAD, defined as a triene:tetraene ratio >0.2. Gestational age-adjusted z scores for length, growth, and head circumference at baseline were compared with the corresponding z scores at time of censoring. All of the patients received PN with a fish oil-based lipid emulsion at 1 g . kg . day as the sole source of fat energy for at least 1 month. The fish oil monotherapy was used under a compassionate use protocol. RESULTS: Median gestational age at the time of birth was 35 weeks, and median age at the start of treatment was 3.5 months. After a median time of 3.8 months on exclusive PN and fish oil-based lipid emulsion, none of the patients developed biochemical or clinical evidence of EFAD. z scores were not statistically different, indicating no growth impairment. Median direct bilirubin levels improved in 9 patients from 6.8 to 0.9 mg/dL (P = 0.009). CONCLUSIONS: : When dosed appropriately, fish oil-based lipid emulsions contain sufficient amounts of essential fatty acids to prevent EFAD and sustain growth in patients who are completely dependent on PN.

Abstract: BACKGROUND: The risk of major hepatic resection in patients with hepatic steatosis remains controversial. A meta-analysis was performed to establish the best estimate of the impact of steatosis on patient outcome following major hepatic surgery. METHODS: A systematic search was performed following Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Risk ratios (RRs) for complication and mortality rates were calculated for patients with no, less than 30 per cent and at least 30 per cent steatosis, and a meta-analysis was carried out. RESULTS: Of six observational studies identified, four including a total of 1000 patients were subjected to meta-analysis; two others were tabulated separately. Compared with patients without steatosis, those with less than 30 per cent and at least 30 per cent steatosis had a significantly increased risk of postoperative complications, with a RR of 1.53 (95 per cent confidence interval (c.i.) 1.27 to 1.85) and 2.01 (1.66 to 2.44) respectively. Patients with at least 30 per cent steatosis had an increased risk of postoperative death (RR 2.79, 95 per cent c.i. 1.19 to 6.51). CONCLUSION: Patients with steatosis had an up to twofold increased risk of postoperative complications, and those with excessive steatosis had an almost threefold increased risk of death.

Abstract: Nonalcoholic fatty liver disease results from overconsumption and is a significant and increasing cause of liver failure. The type of diet that is conducive to the development of this disease has not been established, and evidence-based treatment options are currently lacking. We hypothesized that the onset of hepatic steatosis is linked to the consumption of a diet with a high fat content, rather than related to excess caloric intake. In addition, we also hypothesized that fully manifested hepatic steatosis could be reversed by reducing the fat percentage in the diet of obese mice. C57BL/6J male mice were fed either a purified rodent diet containing 10% fat or a diet with 60% of calories derived from fat. A pair-feeding design was used to distinguish the effects of dietary fat content and caloric intake on dietary-induced hepatic lipid accumulation and associated injury. Livers were analyzed by quantitative reverse transcriptase polymerase chain reaction for lipid metabolism-related gene expression. After 9 weeks, mice on the 60%-fat diet exhibited more weight gain, insulin resistance, and hepatic steatosis compared with mice on a 10%-fat diet with equal caloric intake. Furthermore, mice with established metabolic syndrome at 9 weeks showed reversal of hepatic steatosis, insulin resistance, and obesity when switched to a 10%-fat diet for an additional 9 weeks, independent of caloric intake. Quantitative reverse transcriptase polymerase chain reaction revealed that transcripts related to both de novo lipogenesis and increased uptake of free fatty acids were significantly up-regulated in mice pair-fed a 60%-fat diet compared with 10%-fat-fed animals. Dietary fat content, independent from caloric intake, is a crucial factor in the development of hepatic steatosis, obesity, and insulin resistance in the C57BL/6J diet-induced obesity model caused by increased uptake of free fatty acids and de novo lipogenesis. In addition, once established, all these features of the metabolic syndrome can be successfully reversed after switching obese mice to a diet low in fat. Low-fat diets deserve attention in the investigation of a potential treatment of patients with nonalcoholic fatty liver disease.

Abstract: OBJECTIVES: To update knowledge on the management of parenteral nutrition-associated liver disease (PNALD) and to review the clinical data on the use of parenteral fish oil for reversal of PNALD. DATA SOURCES: A literature review was conducted by searching the MEDLINE database (May 1, 2009) using the keywords parenteral nutrition-associated liver disease, fish oil, omega-3, Omegaven, and lipid emulsion. STUDY SELECTION: All articles reporting clinical cases with the use of parenteral fish oil for management of PNALD. DATA EXTRACTION: Three reviewers independently analyzed the epidemiological, clinical, and treatment data of the articles. DATA SYNTHESIS: Six case reports (10 patients) and 2 cohort studies (12 and 18 patients) were analyzed. CONCLUSIONS: Fish oil-derived emulsions have been demonstrated to reverse preexisting PNALD and to prevent and treat essential fatty acid deficiency. Its ability to prevent PNALD is currently under investigation. Although the mechanism has yet to be fully understood, the advantages of fish oil-based lipid emulsions over soybean oil-based lipid emulsions seen to date suggest that fish oil-based emulsions would be better suited for use in long-term parenteral nutrition.

Abstract: OBJECTIVE: The objective was to determine the safety and efficacy of a fish oil-based intravenous lipid emulsion (ILE) in the treatment of parenteral nutrition-associated liver disease (PNALD). SUMMARY AND BACKGROUND DATA: PNALD can be a lethal complication in children with short bowel syndrome (SBS). ILE based on soybean oil administered with parenteral nutrition (PN) may contribute to its etiology. METHODS: We performed an open-labeled trial of a fish oil-based ILE in 42 infants with SBS who developed cholestasis (serum direct bilirubin >2 mg/dL) while receiving soybean oil-based ILE. Safety and efficacy outcomes were compared with those from a contemporary cohort of 49 infants with SBS and cholestasis whose PN course included soybean ILE only. The primary efficacy end-point was time to reversal of cholestasis (direct bilirubin <=2 mg/dL). RESULTS: Three deaths and 1 liver transplantation occurred in the fish oil cohort, compared with 12 deaths and 6 transplants in the soybean oil cohort (P = 0.005). Among survivors not transplanted during PN, cholestasis reversed while receiving PN in 19 of 38 patients in the fish oil cohort versus 2 of 36 patients in the soybean oil cohort. Based on Cox models, subjects receiving fish oil-based ILE experienced reversal of cholestasis 6 times faster (95% CI: 2.0-37.3) than those receiving soybean oil-based ILE. The provision of fish oil-based ILE was not associated with hypertriglyceridemia, coagulopathy, or essential fatty acid deficiency. Moreover, hypertriglyceridemic events and abnormal international normalized ratio levels were more common among controls. CONCLUSIONS: Fish oil-based ILE is safe, may be effective in treating PNALD, and may reduce mortality and organ transplantation rates in children with SBS.

Abstract: OBJECTIVE: The purpose of this review is to correlate the clinical finding that patients receiving parenteral nutrition with a fish oil-based lipid emulsion do not develop essential fatty acid deficiency (EFAD) with an experimental murine model, thus showing that arachidonic acid (AA) and docosahexaenoic acid (DHA) are likely to be the essential fatty acids. BACKGROUND: Conventional belief is that linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) are the essential fatty acids (EFAs). We have shown that a fish oil-based lipid emulsion containing AA (omega-6) and docosahexaenoic acid (omega-3) and insignificant quantities of LA and ALA is efficacious in the treatment of parenteral nutrition-associated liver disease (PNALD), a major cause of liver-related morbidity and mortality. The prospect of using a fish oil-based lipid emulsion as monotherapy has raised concerns of EFAD development, hindering its adoption into clinical practice. DESIGN: Data from patients in our institution who received PN with a fish oil-based lipid emulsion was reviewed for clinical and biochemical evidence of EFAD, defined as an elevated triene-tetraene ratio (Mead acid/AA>0.2). We also investigated the minimum amount of fish oil required to prevent EFAD in a murine model and determined whether DHA and AA alone can prevent EFAD. RESULTS: No patients receiving PN with a fish oil-based lipid emulsion in our institution have developed biochemical or clinical evidence of EFAD such as an elevated triene-tetraene ratio, growth retardation or dermatitis. This observation parallels our previously published animal studies, which demonstrated prevention of EFAD when 13% of total calories were from fish oil. Moreover, current work in our laboratory shows that AA and DHA provision alone is sufficient to prevent biochemical and physiologic evidence of EFAD in a murine model. CONCLUSIONS: When dosed appropriately, fish oil-based lipid emulsions contain sufficient EFAs to prevent EFAD. Furthermore, AA and DHA alone may be the true EFAs.

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Abstract: Parenteral nutrition-associated liver disease (PNALD) is the most prevalent and most severe complication of long-term parenteral nutrition. Its underlying pathophysiology, however, largely remains to be elucidated. The currently approved parenteral lipid emulsions in the United States contain safflower or soybean oils, both rich in omega-6 polyunsaturated fatty acids (PUFAs). Mounting evidence indicates that the omega-6 PUFAs originating from plant oils in these lipid emulsions may play a role in the onset of liver injury. Fish oil-based lipid emulsions, in contrast, are primarily composed of omega-3 PUFAs, thus providing a promising alternative. The authors review the literature on the role of lipid emulsions in the onset of PNALD and discuss prevention and treatment strategies using a fish oil-based lipid emulsion. They conclude that a fish oil-based emulsion is hepatoprotective in a murine model of PNALD, and it appears to be safe and efficacious for the treatment of this type of liver disease in children. A prospective randomized trial that is currently under way at the authors' institution will objectively determine the place of fish oil monotherapy in the prevention of PNALD.

Abstract: Hernias of the diaphragm are rarely reported as a complication of abdominal surgery. We review a case of a 47-year-old female who presented with dyspnoea and chest pain one day after left radical nephrectomy for renal cell carcinoma. Plain and cross-sectional imaging identified a large left-sided diaphragmatic hernia containing omentum, spleen, splenic flexure, and stomach. Our patient underwent a thoracotomy and, after hernia reduction, the diaphragmatic defect was repaired using non-absorbable sutures and a mesh. She made an uneventful recovery. The potential cause is discussed and the published literature on this rare complication is reviewed briefly.

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Abstract: PURPOSE: This study evaluated the values of transcutaneous oxygen tension (TcPo(2)) measurement in diabetic patients compared with nondiabetic patients and assessed its reproducibility. METHODS: In 60 diabetic patients (type 1 and type 2 diabetes mellitus) without signs of peripheral arterial disease or neuropathy, we measured TcPo(2) at the chest and foot and compared these measurements with 60 age- and sex-matched nondiabetic patients in a cross-sectional fashion. The reproducibility of TcPo(2) in terms of interobserver variability was also assessed. RESULTS: Diabetic patients had a mean +/- SD TcPo(2) value at the foot of 50.02 +/- 8.92 mm Hg, which was significantly lower compared with 56.04 +/- 8.80 mm Hg in nondiabetic patients (P < .001). At the chest wall, values for TcPo(2) were 51.77 +/- 11.15 mm Hg, and 58.22 +/- 12.47 mm Hg for diabetic patients and nondiabetic patients, respectively (P = .003). Regression analysis showed that TcPo(2)was significantly associated with diabetes mellitus (coefficient = -0.258; P = .004), and with having a first-degree relative with diabetes mellitus (coefficient = -0.265; P = .003). Furthermore, the interobserver variability showed a substantial correlation for both measurements at the chest (P < .001; r = 0.654; intraclass correlation coefficient [ICC] = 0.79) and at the dorsum of the foot (P < .001; r = 0.426; ICC = 0.60). CONCLUSION: Diabetic patients without signs of peripheral disease or neuropathy had significantly lower TcPo(2) values compared with age- and sex-matched nondiabetic patients. The influence of the examiner on the variance in TcPo(2) measurements was relatively small. We advocate the use of TcPo(2) measurement in diabetic patients to detect subclinical microvascular impairment as an additional tool to assess peripheral vascular disease.

Abstract: Casus Een 39-jarige vrouw presenteerde zich op de afdeling spoedeisende hulp in verband met een progressief krampende pijn rechts onder in de buik sinds enkele dagen. De pijn was niet gerelateerd aan de menstruatie, welke overigens bij oraal anticonceptiegebruik regelmatig verliep. Lichamelijk onderzoek toonde een groot vast-elastisch, enigszins beweeglijk ruimte innemend proces in de suprapubische regio. Er werd geen druk- of loslaatpijn geconstateerd en bij rectaal toucher werden geen palpabele afwijkingen gevoeld. Vaginaal toucher werd niet verricht. Bloed en urine waren inmiddels afgenomen en in verband met de verdenking op coprostase werd een buikoverzichtsfoto verricht (foto). De foto toonde een foetus in utero. Echografie stelde een zwangerschapsduur van ruim 30 weken vast. Het bloedbeeld toonde achteraf een verhoogde bezinking en verlaagd Hb, suggestief voor een zwangerschap. Tevens was de verrichte zwangerschaptest positief. Beschouwend is de buikoverzichtsfoto in een te vroeg stadium verricht. De ‘pitt fall’ was echter dat een zwangerschap anamnestisch wel overwogen was, maar door deze nulligravida resoluut werd ontkend. Bovendien maakte het ontbreken van duidelijke subjectieve zwangerschapsverschijnselen, alsmede het niet uitblijven van de menstruatie, de diagnose zwangerschap minder waarschijnlijk. Specifiek vragen naar een kortere menstruatieduur met duidelijk minder bloedverlies had mogelijkerwijs wel tot de juiste diagnose geleid. Ioniserende straling kan, afhankelijk van de dosis en het moment, abnormale celdood induceren en cytogenetische afwijkingen en somatische mutaties veroorzaken. Hoewel het in deze casus gezien de gevorderde zwangerschapsduur en geringe stralingsbelasting onwaarschijnlijk is, kan ioniserende straling met name in het eerste trimester leiden tot congenitale afwijkingen, intra-uteriene vruchtdood en groeiretardatie. Daarom moet op een spoedeisende hulp bij vrouwen met buikklachten en het geringste vermoeden op een zwangerschap te allen tijde een zwangerschapstest afgenomen én de uitslag afgewacht worden, alvorens hen bloot te stellen aan potentieel schadelijke straling. Diagnose: Zwangerschap.

Abstract: 2-Deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography (PET) is an established imaging modality in the fields of clinical oncology, cardiology and neurology, and could be useful for the diagnosis of vascular prosthetic graft infection. The technology of combining FDG-PET and computed tomography (CT) images, acquired in a single session, is gaining popularity. Several reports proposed the application of both FDG-PET and FDG-PET/CT in the diagnosis and management of vascular prosthetic graft infection. This case report highlights the usefulness of FDG-PET and FDG-PET/CT as noninvasive diagnostic modalities for patients with multiple vascular prosthetic bypass grafts susceptible for infection.

Abstract: The aims of this study were to assess the technical effectiveness of radiofrequency (RF) ablation in patients with primary or secondary hepatic malignancies and to determine survival and complication rates. This was a retrospective analysis of prospectively collected data of patients treated with RF ablation and controlled for recurrence every 3 months by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). The outcome is compared with a comprehensive review of data published in recent literature. Forty-seven patients underwent 50 RF sessions for the ablation of 73 tumors. Local tumor progression was observed in 11 patients (23%). A tumor sized larger than 30 mm, a tumor load larger than 14 cm3, and a percutaneous approach were associated with a faster time to local tumor progression. At the end of a mean (+/- SD) follow-up period of 11.4 +/- 7.5 months, 39 patients (83%) were alive, including eight patients with recurrent disease. The overall cumulative survival rates at 12 and 24 months were 87% and 70%, respectively. In our center, RF ablation can be safely performed to achieve adequate local control and survival rates. Time to local tumor progression was significantly related to initial size of the tumor and tumor load.