Current status of lipid emulsions in the prevention of intestinal failure-associated liver disease.

PURPOSE OF REVIEW: The current review provides a summary of available lipid products and discusses current literature and the limitations to the use of various lipid products for treatment and prevention of intestinal failure-associated liver disease (IFALD) in pediatric patients dependent on parenteral nutrition. RECENT FINDINGS: Improvements in markers of cholestasis and liver function have been seen with minimizing soybean lipid, fish oil lipid, and mixed fish oil-containing lipid emulsions. Soybean-based lipid products are thought to be the biggest contributor to development of IFALD. Mixed fish oil-containing lipid emulsions are most promising for minimizing and improving IFALD. SUMMARY: Several types of lipid-based products are available for parenteral nutrition. Newer products like the mixed fish oil-containing-based lipid emulsions, that closely mimic the lipid composition provided by enteral feeding, may impact prevention and treatment of IFALD. Limitations exist in the current literature regarding mixed fish oil-containing-based emulsions, as many of the studies were designed to show efficacy with regard to growth, not prevention or treatment of IFALD. Based on available literature, it is reasonable to make some recommendations with regard to product selection for lipid provision.

Long-Term Outcomes in Children With Intestinal Failure-Associated Liver Disease Treated With 6 Months of Intravenous Fish Oil Followed by Resumption of Intravenous Soybean Oil.

BACKGROUND: Intravenous soybean oil (SO) is a commonly used lipid emulsion for children with intestinal failure (IF); however, it is associated with IF-associated liver disease (IFALD). Studies have demonstrated that intravenous fish oil (FO) is an effective treatment for IFALD. However, there is a lack of long-term data on children who stop FO and resume SO. This study's objective was to investigate our institution's outcomes for children with IFALD treated with 6 months of FO and who then restarted SO. METHODS: Inclusion criteria for FO included children with IFALD. Parenteral nutrition (PN)-dependent children resumed SO after FO and were prospectively followed for 4.5 years or until death, transplant, or PN discontinuation. The primary outcome was the cumulative incidence rate (CIR) for cholestasis after FO. RESULTS: Forty-eight subjects received FO, and conjugated bilirubin decreased over time (-0.22 mg/dL/week; 95% confidence interval [CI]: -0.25, -0.19; P < .001). The CIR for cholestasis resolution after 6 months of FO was 71% (95% CI: 54%, 82%). Twenty-seven subjects resumed SO and were followed for a median of 16 months (range 3-51 months). While the CIR for enteral autonomy after 3 years of follow-up was 40% (95% CI: 17%, 26%), the CIR for cholestasis and transplant was 26% (95% CI: 8%, 47%) and 6% (95% CI: 0.3%, 25%), respectively. CONCLUSION: In this study, FO effectively treated cholestasis, and SO resumption was associated with cholestasis redevelopment in nearly one-fourth of subjects. Long-term FO may be warranted to prevent end-stage liver disease.

[Portal vein embolization: Present and future]. / Embolisation portale préopératoire : présent et futur.

Portal vein embolization consists of occluding a part of the portal venous system in order to achieve the hypertrophy of the non-embolized liver segments. This technique is used during the preoperative period of major liver resection when the future remnant liver (FRL) volume is insufficient, exposing to postoperative liver failure, main cause of death after major hepatectomy. Portal vein embolization indication depends on the FRL, commonly assessed by its volume. Nowadays, FRL function evaluation seems more relevant and can be measured by 99mTc labelled mebrofenin scintigraphy. Portal vein embolization procedure is mostly performed with percutaneous trans-hepatic access by using ultrasonography guidance and consists of embolic agent injection, such as cyanoacrylate, in the targeted portal vein branches with fluoroscopic guidance. It is a safe and well-tolerated technique, with extremely low morbi-mortality. Portal vein embolization leads to sufficient FRL hypertrophy in about 80% of patients, allowing them to undergo surgery from which they were initially rejected. The two main reasons of non-resection are tumor progression (≈15% of cases) and FRL insufficient hypertrophy (≈5% of cases). When portal vein embolization is not enough to obtain adequate FRL regeneration, hepatic vein embolization may potentiate its effect (liver venous deprivation technique).

Aqueous calyxes extract of Roselle or Hibiscus sabdariffa Linn supplementation improves liver morphology in streptozotocin induced diabetic rats.

BACKGROUND AND STUDY AIMS: The complex series of deleterious events among diabetes patients leads to multiple organ failure. Therefore, a holistic approach of treatment is urgently required to prevent worsening of complications. The present investigation was carried out to study the possible protective effects of Roselle or Hibiscus sabdariffa Linn (HSL) calyxes aqueous extract, as an antidiabetic and antioxidant agent against oxidative liver injury in streptozotocin-induced diabetic rats. MATERIAL AND METHODS: A single dose of streptozotocin (45mg/kg body weight, iv) was used to induced diabetes in male Sprague Dawley rats which were then divided into two groups: Diabetic control (DC) and HSL-treated diabetic (DR) group. Normal rats were divided into normal control (NC), HSL-treated control (NR). Aqueous calyxes extract of HSL (100mg/kg/day, orally) was given for 28 consecutive days in the treated group. Weight, biochemical and histopathological (light and electron microscopic) parameters were compared in all groups. RESULTS: Supplementation of HSL significantly lowered the level of fasting blood glucose and increased plasma insulin level in DR group compared to DC group (p<0.05). Alanine aminotransaminases and aspartate aminotransferase enzymes level were found to be significantly reduced in DR compared to DC. Microscopic examination demonstrated destruction of the liver architecture, cytoplasmic vacuolation of the hepatocytes and signs of necrosis in diabetic rats. Moreover, dilatation and congestion of blood vessels with leucocytes adherence were detected. Ultrastructural study using electron microscope showed homogeneous substance accumulation in nuclear chromatin, a decrease of organelles and mitochondrial degeneration in the diabetic rats. CONCLUSION: Administration of HSL in diabetic rats causes significant decrease in hepatocyte destruction and prevented the changes associated with the diabetic condition. Thus, our findings provide a scientific rationale for the use of HSL as promising agent in preventing liver injury in diabetes.

Low-dose polymyxin: an option for therapy of Gram-negative sepsis.

Endotoxins are the major components of the outer membrane of most Gram-negative bacteria and are one of the main targets in inflammatory diseases. The presence of endotoxins in blood can provoke septic shock in case of pronounced immune response. Here we show in vitro inactivation of endotoxins by polymyxin B (PMB). The inflammatory activity of the LPS-PMB complex in blood was examined in vitro in freshly drawn blood samples. Plasma protein binding of PMB was determined by ultracentrifugation using membranes with different molecular cut-offs, and PMB clearance during dialysis was calculated after in vitro experiments using the AV1000S filter. The formed LPS-PMB complex has lower inflammatory activity in blood, which results in highly reduced cytokine secretion. According to in vitro measurements, the appropriate plasma level of PMB for LPS inactivation is between 100 and 200 ng/ml. Furthermore, the combination of cytokine removal by adsorbent treatment with LPS inactivation by PMB dosage leads to strong suppression of inflammatory effects in blood in an in vitro model. Inactivation of endotoxins by low-dose intravenous PMB infusion or infusion into the extracorporeal circuit during blood purification can be applied to overcome the urgent need for endotoxin elimination not only in treatment of sepsis, but also in liver failure.

Normal Growth and Essential Fatty Acid Status in Children With Intestinal Failure on Lipid Limitation.

OBJECTIVES: Lipid limitation, that is, ≤1 g · kg⁻¹ · day⁻¹ of soy oil lipid emulsion (SOLE), has been suggested as a method to reduce the risk of intestinal failure (IF)-associated liver disease (IFALD). There are limited data as to the effects of this strategy on growth and essential fatty acid (EFA) status. The aim of the study was to assess growth, prevalence of cholestasis, and EFA deficiency in patients with IF who were provided daily SOLE at a dose ≤1 g · kg⁻¹ · day⁻¹. METHODS: Medical records were retrospectively reviewed from 9 patients age 16 months to 8 years who had IF requiring parenteral nutrition support for >12 months. Parenteral nutrition supplied a mean of 53% of total energy (range 24%-86%). RESULTS: Mean SOLE dose was 0.61 g · kg⁻¹ · day⁻¹ (range 0.4-0.81 g · kg⁻¹ · day⁻¹). After 1 month of lipid limitation between 2011 and 2014, no patient developed IFALD as defined by a direct bilirubin >2 mg/dL. The median direct bilirubin was 0.1 mg/dL (range 0.075-0.85 mg/dL). No patient developed EFA deficiency as defined by a triene-to-tetraene ratio >0.2 (median 0.026, range 0.017-0.076). Height z scores increased from mean of -2.568 (range -10.8 to 0.878) to -0.484 (range -3.546 to 0.822). Weight z scores increased from mean of -1.412 (range -5.871 to 0.906) to -0.595 (range -2.178 to 0.926). CONCLUSIONS: In this case series, lipid limitation allowed normal growth while preventing the development of cholestasis and EFA deficiency.

ß-Caryophyllene alleviates D-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the TLR4 and RAGE signaling pathways.

Agastache rugosa (A. rugosa, Labiatae), a perennial herb spread throughout Korean fields, is widely consumed as a wild edible vegetable and is used in folk medicine. This study examined the hepatoprotective mechanisms of ß-caryophyllene (BCP), a major bicyclic sesquiterpene of A. rugosa, against D-galactosamine (GalN) and lipopolysaccharide (LPS)-induced hepatic failure. Mice were given an intraperitoneal injection of BCP (50, 100 and 200 mg/kg) 1 h before GalN (800 mg/kg)/LPS (40 µg/kg) injection and were killed 1 h or 6 h after GalN/LPS injection. GalN/LPS markedly increased mortality and serum aminotransferase activity, both of which were attenuated by BCP. BCP also attenuated increases in serum tumor necrosis factor-α, interleukin 6, and high-mobility group protein B1 levels by GalN/LPS. GalN/LPS significantly increased toll-like receptor (TLR) 4 and receptor for advanced glycation end products (RAGE) protein expression, extracellular signal-related kinase, p38 and c-Jun N-terminal kinase phosphorylation, nuclear factor κB (NF-κB), early growth response protein-1, and macrophage inflammatory protein-2 protein expression. These increases were attenuated by BCP. Furthermore, BCP suppressed increased TLR4 and RAGE protein expression and proinflammatory cytokines production in LPS-treated isolated Kupffer cells. Our findings suggest that BCP protects against GalN/LPS-induced liver injury through down-regulation of the TLR4 and RAGE signaling.

Cilostazol improves hepatic blood perfusion, microcirculation, and liver regeneration after major hepatectomy in rats.

Major hepatectomy or small-for-size liver transplantation may result in postoperative liver failure. So far, no treatment is available to improve liver regeneration. Herein, we studied whether cilostazol, a selective phosphodiesterase III inhibitor, is capable of improving liver regeneration after major hepatectomy. Sprague-Dawley rats (n = 74) were treated with cilostazol (5 mg/kg daily) or a glucose solution and underwent either 70% liver resection or a sham operation. Before and after surgery, hepatic arterial and portal venous blood flow and hepatic microvascular perfusion were analyzed. Liver morphology, function, and regeneration were studied with histology, immunohistochemistry, western blotting, and bile excretion analysis. Cilostazol significantly increased hepatic blood flow and microcirculation before and after hepatectomy in comparison with sham-operated controls. This was associated with an elevation of hepatic vascular endothelial growth factor expression, an increase of hepatocellular proliferation, and an acceleration of liver regeneration. Furthermore, cilostazol protected the tissue of the remnant liver as indicated by an attenuation of hepatocellular disintegration. In conclusion, cilostazol increases hepatic blood perfusion, microcirculation, and liver regeneration after a major hepatectomy. Thus, cilostazol may represent a novel strategy to reduce the rate of liver failure after both extended hepatectomy and small-for-size liver transplantation.

Thrombomodulin improves rat survival after extensive hepatectomy.

BACKGROUND: Recombinant human soluble thrombomodulin (rTM) protects against disseminated intravascular coagulopathy by inhibiting coagulation, inflammation, and apoptosis. This study tests the hypothesis that rTM is hepatoprotective after extensive hepatectomy (Hx) and investigates the mechanisms underlying this effect. MATERIALS AND METHODS: Experiment 1: rats (15 per group) were injected with rTM (1.0 or 2.0 mg/kg) or saline just before 95% Hx and their 7-d survival assessed. Experiment 2: rats were assigned to either a treated (2.0 mg/kg rTM just before Hx) or control group (n = 5 per group). Five rats per group were euthanized immediately after surgery, and at 1, 3, 6, 12, and 24 h postoperatively; serum and liver remnant samples were collected for biochemical and histologic analysis, as well as reverse-transcription polymerase chain reaction and Western blotting. RESULTS: All saline-injected rats died within 52 h of Hx, whereas injection of 2.0 mg/kg rTM prolonged survival (P = 0.003). rTM increased the number of Ki67-positive cells and reduced the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. The number of myeloperoxidase-positive cells and the expression of high-mobility group box 1 protein did not differ. Reverse-transcription polymerase chain reaction revealed that rTM significantly enhanced protease-activated receptor-1 and sphingosine kinase 1 messenger RNA expression and significantly reduced plasminogen activator inhibitor-1 and Bax messenger RNA expression. Immunohistochemistry and Western blotting demonstrated that protease-activated receptor-1 expression 24 h after Hx was significantly higher in rTM-treated than in control rats. CONCLUSIONS: rTM may improve survival after extensive Hx by inhibiting apoptosis and promoting liver regeneration.

Effect of olprinone on liver microstructure in rat partial liver transplantation.

BACKGROUND: Donor safety is a major concern in living-donor liver transplantation. However, partial grafts do not meet the functional demands of recipients and lead to small-for-size syndrome (SFSS). In a previous study, we showed that olprinone (OLP), a selective phosphodiesterase ІІІ inhibitor, up-regulates endothelial nitric oxide synthase level in the liver and attenuates shear stress, sinusoidal endothelial cell injury, and hepatocyte apoptosis after excessive liver resection in a rat model. We aimed to examine whether OLP treatment has beneficial effects on SFSS in a rat model of partial liver transplantation (PLT). METHODS: We performed experiments in a rat model of 30% PLT. In the OLP group, we inserted an osmotic pump with OLP into the peritoneal cavity 48 h before liver graft sampling. Recipient rats were not treated with OLP. We examined the liver microstructure by electron microscopy and biochemical examination, and determined the 7-d survival of recipients. RESULTS: In the OLP group 1 h after PLT, the sinusoidal endothelial cells of the liver were well preserved and we observed few vacuolar structures in hepatocytes. The total serum bilirubin level 1 wk after PLT tended to be lower in the OLP group than in the controls, and the liver microstructures were also well preserved in the OLP group. The probability of survival in the OLP group (100%; 14 of 14 rats) was significantly higher than that in the control group (75%; 15 of 20 rats). CONCLUSIONS: Olprinone treatment was demonstrated to have therapeutic potential to overcome SFSS.

Prevention and reversal of intestinal failure-associated liver disease in premature infants with short bowel syndrome using intravenous fish oil in combination with omega-6/9 lipid emulsions.

Although premature infants with short bowel syndrome are at the highest risk of developing intestinal failure-associated liver disease (IFALD), they have great capacity for intestinal growth and adaptation if IFALD can be prevented. Conventional soybean oil-based intravenous lipid emulsions have been associated with IFALD. This study presents data on 5 premature neonates with short bowel syndrome treated with a combination of parenteral fish oil- and olive/soybean-based lipid emulsion for periods ranging between 7 and 17 months. Despite an enteral tolerance of less than 50% in 4 of these patients during their first year of life, direct bilirubin levels normalized while on this combination of ClinOleic (Baxter, Maurepas, France)/Omegaven (Fresenius Kabi, Bad Homburg, Germany) at a 1:1 ratio. None of our patients developed irreversible IFALD even though all of them were premature, had undergone multiple major surgical procedures, and had experienced several episodes of sepsis. Thus far, we have not seen any adverse effects of this mixed lipid emulsion in these preterm infants. All 5 patients are growing and developing well and have normal liver function.

Comparison of 5 intravenous lipid emulsions and their effects on hepatic steatosis in a murine model.

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. ω-3 fatty acids may be efficacious in preventing PNALD and should be explored in the development of novel lipid emulsions.

Protective effect of Amaranthus spinosus against D-galactosamine/lipopolysaccharide-induced hepatic failure.

The current study is an effort to identify the hepatoprotective activity of the 50% ethanol extract of the whole plant of Amaranthus spinosus Linn. (Amaranthaceae) against d-galactosamine/lipopolysaccharide (d-GalN/LPS)-induced liver injury in rats. d-GalN/LPS (300 mg/kg body weight/30 µg/kg body weight)-induced hepatic damage was manifested by a significant (p <0.05) increase in the activities of marker enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase and gamma glutamyl transferase) and bilirubin level in serum while phospholipids significantly decreased. All other parameters, i.e. cholesterol, triglycerides and free fatty acids were increased significantly in both serum and liver compared to the control group. Pretreatment of rats with A. spinosus extract (400 mg/kg) significantly (p <0.05) reversed these altered parameters to normal compared to the intoxicated group. The biochemical observations were supplemented by histopathological examination of liver sections. There were no significant changes in the activities of marker enzymes, bilirubin level and lipids in the rats treated with A. spinosus extract alone. Results of this study revealed that A. spinosus extract could afford a significant protection against d-GalN/LPS-induced hepatocellular injury.

Is the use of parenteral omega-3 lipid emulsions justified in surgical neonates with mild parenteral nutrition-associated liver dysfunction?

PURPOSE: Although evidence suggests that parenteral omega-3 lipid emulsions (O-3LEs) may be beneficial in treating advanced parenteral nutrition (PN)-associated liver disease, our objective was to determine if O-3LEs are justified in those with early liver disease. METHODS: This is a retrospective analysis of prospectively collected data on all surgical neonates, who received more than 1 day of PN postoperatively between 2001 and 2004 with observation through 2005 (era before O-3LE introduction). We examined the proportion of those who developed mild and advanced liver dysfunction. RESULTS: Of the 292 infants in the cohort, 104 (36%) developed mild liver dysfunction (conjugated bilirubin, 34 micromol/L [cBili34]) after a mean of 22 days. Thirty-one (30%) of the cBili34 patients reached a serum conjugated bilirubin of 100 micromol/L, and 13 (13%) developed liver failure. Of these, 4 underwent transplantation, and 5 died of hepatic disease. Overall, 86 of the cBili34 patients (83%) were weaned off PN. CONCLUSION: With more than 80% of cBili34 patients being weaned from PN without adverse hepatic sequelae, it is difficult, in the absence of definitive evidence of efficacy and safety for O-3LEs together with increased costs, to justify the routine use of O-3LEs in this low-risk population outside formal research protocols.

In vitro inhibition of lipopolysaccharide and mycobacterium bovis bacillus Calmette Guérin-induced inflammatory cytokines and in vivo protection from D-galactosamine/LPS -mediated liver injury by the medicinal plant Sclerocarya birrea.

Sclerocarya birrea is a medicinal plant used for the treatment of inflammatory- and bacterial-related diseases. The present study investigated in vitro and in vivo the effects of the stem bark methanol extract of S. birrea. Nitrite, TNF, IL-1beta, IL-6 and IL-12p40 production by bone marrow-derived macrophages (BMDM) pre-incubated with or without S. birrea, and stimulated with Lipopolysaccharide (LPS) or infected with live Mycobacterium bovis Bacillus Calmette Guérin (BCG) was evaluated. S. birrea extract inhibited, in a concentration-dependent manner, nitrite, TNF, IL-1beta, IL-6 and IL-12p40 production by BMDM stimulated with LPS or infected with live BCG. The iNOS expression was reduced by S. birrea after stimulation of BMDM with LPS. In addition, S. birrea inhibited the nuclear factor kB (NF-kB) activation by both LPS and BCG. The effects of the plant extract were also evaluated in an in vivo model of liver injury induced by D-galactosamine/LPS (D-GalN/LPS) administration in mice. S. birrea limited D-GalN/LPS-liver injury as assessed by a reduction in transaminases and TNF, IL-1beta, IL-6 serum levels, and translocation of NF-kB to the nucleus. Taken together, our data indicate that stem bark methanol extract of S. birrea possesses anti-inflammatory properties by inhibiting NF-kB activation and cytokine release induced by inflammatory or infectious stimuli.

Growth factor modulation of hepatic inflammation: a novel approach to the management of total parenteral nutrition-associated liver disease.

PURPOSE: Dependence on total parenteral nutrition in intestinal failure or short bowel syndrome patients can lead to many complications. The most significant complication is progressive liver injury leading to liver failure. This study assesses the potential of hepatocyte growth factor (HGF) in modulating the hepatic response in a rat cholestatic liver injury model. METHODS: Female Sprague-Dawley rats were divided into 3 groups: control (n = 5), chronic liver injury (alpha-naphtylisocyocyanate [ANIT] every 3.5 days at 75 mg/kg; n = 5), and chronic liver injury plus HGF (ANIT + HGF at 250 microg kg(-1) d(-1); n = 5). The rats initially underwent massive (80%) small bowel resections. Seven days later, they were given intraperitoneal injections of saline (control) or ANIT and implantation of an osmotic minipump for continuous intravenous saline or HGF. Intraperitoneal saline or ANIT injections were subsequently administered every 3.5 days to create a chronic cholestatic model. After 14 days, the animals were euthanized, and liver biopsies were obtained. The liver biopsies were evaluated by histology, immunofluorescence staining for interleukin-6 and tumor necrosis factor alpha, and assessment of apoptosis by terminal dUTP-transferase-mediated nick end labeling (TUNEL) technique. RESULTS: In this chronic liver injury model, HGF did not effect the grade of inflammation. However, HGF did induce retention of the ductal structures and avoided ductal proliferation, damage, and evidence of primary sclerosing cholangitis (P < .05). Hepatocyte growth factor induced less interleukin-6 (P < .011) and tumor necrosis factor alpha (P < .01) expression. Apoptotic activity was also significantly less in the HGF group (P < .01). CONCLUSION: Hepatocyte growth factor preserved the hepatic ductal system, modulated the hepatic inflammatory response, and reduced the apoptotic index in this chronic cholestatic liver injury model. It may diminish or prevent liver damage in patients with total parenteral nutrition-induced liver injury.

Rescue treatment of infants with intestinal failure and parenteral nutrition-associated cholestasis (PNAC) using a parenteral fish-oil-based lipid.

Four preterm infants with intestinal failure and severe parenteral nutrition-associated cholestasis (PNAC) received fish-oil-based parenteral lipid as rescue treatment in substitution for the standard soybean-based lipid preparation. The progression of liver disease was halted in 3 infants and they recovered with complete resolution of PNAC. The condition in two of these infants would almost certainly have progressed to end-stage hepatic failure if they had continued to receive long-term parenteral nutrition and <30% of total nutrition enterally. The remaining infant with residual inflamed bowel, protracted feeding intolerance and repeated episodes of sepsis did not respond. Our findings suggest that fish-oil-based parenteral lipid emulsion may contribute to effective treatment of PNAC in selected patients, which should be further evaluated in randomized controlled trials.

Protective effect of daidzin against D-galactosamine and lipopolysaccharide-induced hepatic failure in mice.

This study examined the effects of daidzin, a major isoflavone from Puerariae Radix, on D-galactosamine (D-GalN) and lipopolysaccharide (LPS)-induced liver failure. Mice were given an intraperitoneal injection of daidzin (25, 50, 100 and 200 mg/kg) 1 h before receiving an injection of D-GalN (700 mg/kg)/LPS (10 microg/kg). Daidzin markedly reduced the elevated serum aminotransferase activity and the levels of lipid peroxidation and tumor necrosis factor-alpha. The glutathione content was lower in the D-GalN/LPS group, which was attenuated by daidzin. The daidzin pretreatment attenuated the swollen mitochondria observed in the d-GalN/LPS group. Daidzin attenuated the apoptosis of hepatocytes, which was confirmed using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling method and a caspase-3 assay. Overall, these results suggest that the liver protection of daidzin is due to reduced oxidative stress and its antiapoptotic activity.

Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease.

BACKGROUND: Parenteral nutrition-associated liver disease can be a progressive and fatal entity in children with short-bowel syndrome. Soybean-fat emulsions provided as part of standard parenteral nutrition may contribute to its pathophysiology. METHODS: We compared safety and efficacy outcomes of a fish-oil-based fat emulsion in 18 infants with short-bowel syndrome who developed cholestasis (serum direct bilirubin level of > 2 mg/dL) while receiving soybean emulsions with those from a historical cohort of 21 infants with short-bowel syndrome who also developed cholestasis while receiving soybean emulsions. The primary end point was time to reversal of cholestasis (3 consecutive measurements of serum direct bilirubin level of < or = 2 mg/dL). RESULTS: Among survivors, the median time to reversal of cholestasis was 9.4 and 44.1 weeks in the fish-oil and historical cohorts, respectively. Subjects who received fish-oil-based emulsion experienced reversal of cholestasis 4.8 times faster than those who received soybean emulsions and 6.8 times faster in analysis adjusted for baseline bilirubin concentration, gestational age, and the diagnosis of necrotizing enterocolitis. A total of 2 deaths and 0 liver transplantations were recorded in the fish-oil cohort and 7 deaths and 2 transplantations in the historical cohort. The provision of fish-oil-based fat emulsion was not associated with essential fatty acid deficiency, hypertriglyceridemia, coagulopathy, infections, or growth delay. CONCLUSIONS: Parenteral fish-oil-based fat emulsions are safe and may be effective in the treatment of parenteral nutrition-associated liver disease.