Should possible recurrence of disease contraindicate liver transplantation in patients with end-stage alveolar echinococcosis? A 20-year follow-up study.

Liver transplantation (LT) is currently contraindicated in patients with residual or metastatic alveolar echinococcosis (AE) lesions. We evaluated the long-term course of such patients who underwent LT and were subsequently treated with benzimidazoles. Clinical, imaging, serological, and therapeutic data were collected from 5 patients with residual/recurrent AE lesions who survived for more than 15 years. Since 2004, [(18) F]-2-fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) images were available, and the levels of serum antibodies (Abs) against Echinococcus multilocularis-recombinant antigens were evaluated. Median survival time after LT was 21 years. These patients were from a prospective cohort of 23 patients with AE who underwent LT: 5 of 8 patients with residual/recurrent AE and 4 of 9 patients without residual/recurrent AE were alive in September 2009. High doses of immunosuppressive drugs, the late introduction of therapy with benzimidazoles, its withdrawal due to side effects, and nonadherence to this therapy adversely affected the prognosis. Anti-Em2(plus) and anti-rEm18 Ab levels and standard FDG-PET enabled the efficacy of therapy on the growth of EA lesions to be assessed. However, meaningful variations in Ab levels were observed below diagnostic cutoff values; and in monitoring AE lesions, images of FDG uptake taken 3 hours after its injection were more sensitive than images obtained 1 hour after its injection. In conclusion, benzimidazoles can control residual/recurrent AE lesions after LT. Using anti-rEm18 or anti-Em2(plus) Ab levels and the delayed acquisition of FDG-PET images can improve the functional assessment of disease activity. The potential recurrence of disease, especially in patients with residual or metastatic AE lesions, should not be regarded as a contraindication to LT when AE is considered to be lethal in the short term.

Metabolic alterations and increased liver mTOR expression precede the development of autoimmune disease in a murine model of lupus erythematosus

Although metabolic syndrome (MS) and systemic lupus erythematosus (SLE) are often associated, a common link has not been identified. Using the BWF1 mouse, which develops MS and SLE, we sought a molecular connection to explain the prevalence of these two diseases in the same individuals. We determined SLE- markers (plasma anti-ds-DNA antibodies, splenic regulatory T cells (Tregs) and cytokines, proteinuria and renal histology) and MS-markers (plasma glucose, non-esterified fatty acids, triglycerides, insulin and leptin, liver triglycerides, visceral adipose tissue, liver and adipose tissue expression of 86 insulin signaling-related genes) in 8-, 16-, 24-, and 36-week old BWF1 and control New-Zealand-White female mice. Up to week 16, BWF1 mice showed MS-markers (hyperleptinemia, hyperinsulinemia, fatty liver and visceral adipose tissue) that disappeared at week 36, when plasma anti-dsDNA antibodies, lupus nephritis and a pro-autoimmune cytokine profile were detected. BWF1 mice had hyperleptinemia and high splenic Tregs till week 16, thereby pointing to leptin resistance, as confirmed by the lack of increased liver P-Tyr-STAT-3. Hyperinsulinemia was associated with a down-regulation of insulin related-genes only in adipose tissue, whereas expression of liver mammalian target of rapamicyn (mTOR) was increased. Although leptin resistance presented early in BWF1 mice can slow-down the progression of autoimmunity, our results suggest that sustained insulin stimulation of organs, such as liver and probably kidneys, facilitates the over-expression and activity of mTOR and the development of SLE.

Successful domino liver transplantation in maple syrup urine disease using a related living donor

Maple syrup urine disease (MSUD) is an autosomal recessive disease associated with high levels of branched-chain amino acids. Children with MSUD can present severe neurological damage, but liver transplantation (LT) allows the patient to resume a normal diet and avoid further neurological damage. The use of living related donors has been controversial because parents are obligatory heterozygotes. We report a case of a 2-year-old child with MSUD who underwent a living donor LT. The donor was the patient's mother, and his liver was then used as a domino graft. The postoperative course was uneventful in all three subjects. DNA analysis performed after the transplantation (sequencing of the coding regions of BCKDHA, BCKDHB, andDBT genes) showed that the MSUD patient was heterozygous for a pathogenic mutation in the BCKDHB gene. This mutation was not found in his mother, who is an obligatory carrier for MSUD according to the family history and, as expected, presented both normal clinical phenotype and levels of branched-chain amino acids. In conclusion, our data suggest that the use of a related donor in LT for MSUD was effective, and the liver of the MSUD patient was successfully used in domino transplantation. Routine donor genotyping may not be feasible, because the test is not widely available, and, most importantly, the disease is associated with both the presence of allelic and locus heterogeneity. Further studies with this population of patients are required to expand the use of related donors in MSUD.

Cyst infection in hospital-admitted autosomal dominant polycystic kidney disease patients is predominantly multifocal and associated with kidney and liver volume

Positron-emission tomography/computed tomography (PET/CT) has improved cyst infection (CI) management in autosomal dominant polycystic kidney disease (ADPKD). The determinants of kidney and/or liver involvement, however, remain uncertain. In this study, we evaluated clinical and imaging factors associated with CI in kidney (KCI) and liver (LCI) in ADPKD. A retrospective cohort study was performed in hospital-admitted ADPKD patients with suspected CI. Clinical, imaging and surgical data were analyzed. Features of infected cysts were evaluated by PET/CT. Total kidney (TKV) and liver (TLV) volumes were measured by CT-derived multiplanar reconstruction. CI was detected in 18 patients who experienced 24 episodes during an interval of 30 months (LCI in 12, KCI in 10 and concomitant infection in 2). Sensitivities of CT, magnetic resonance imaging and PET/CT were 25.0, 71.4, and 95.0%. Dysuria (P<0.05), positive urine culture (P<0.01), and previous hematuria (P<0.05) were associated with KCI. Weight loss (P<0.01) and increased C-reactive protein levels (P<0.05) were associated with LCI. PET/CT revealed that three or more infected cysts were present in 70% of the episodes. TKV was higher in kidney-affected than in LCI patients (AUC=0.91, P<0.05), with a cut-off of 2502 mL (72.7% sensitivity, 100.0% specificity). TLV was higher in liver-affected than in KCI patients (AUC=0.89, P<0.01) with a cut-off of 2815 mL (80.0% sensitivity, 87.5% specificity). A greater need for invasive procedures was observed in LCI (P<0.01), and the overall mortality was 20.8%. This study supports PET/CT as the most sensitive imaging method for diagnosis of cyst infection, confirms the multifocal nature of most hospital-admitted episodes, and reveals an association of kidney and liver volumes with this complication.

Daily consumption of an aqueous green tea extract supplement does not impair liver function or alter cardiovascular disease risk biomarkers in healthy men

Regular consumption of green tea polyphenols (GTP) is thought to reduce the risk of cardiovascular disease (CVD) but has also been associated with liver toxicity. The present trial aimed to assess the safety and potential CVD health beneficial effects of daily GTP consumption. We conducted a placebo-controlled parallel study to evaluate the chronic effects of GTP on liver function and CVD risk biomarkers in healthy men. Volunteers (treatment: n = 17, BMI 26.7 +/- 3.3 kg/m(2), age 41 +/- 9 y; placebo, n = 16, BMI 25.4 +/- 3.3 kg/m(2), age 40 +/- 10 y) consumed for 3 wk 6 capsules per day (2 before each principal meal) containing green tea extracts (equivalent to 714 mg/d GTP) or placebo. At the beginning and end of the intervention period, we collected blood samples from fasting subjects and measured vascular tone using Laser Doppler lontophoresis. Biomarkers of liver function and CVD risk (including blood pressure, plasma lipids, and asymmetric dimethylarginine) were unaffected by GTP consumption. After treatment, the ratio of total:HDL cholesterol was significantly reduced in participants taking GTP capsules compared with baseline. Endothelial-dependent and -independent vascular reactivity did not significantly differ between treatments. In conclusion, the present data suggests that the daily consumption of high doses of GTP by healthy men for 3 wk is safe but without effects on CVD risk biomarkers other than the total:HDL cholesterol ratio. J. Nutr. 139: 58-62, 2009.

Alveolar hydatid disease (Echinococcus multilocularis) in the liver of a Canadian dog in British Columbia, a newly endemic region.

An adult dog that lived in central British Columbia was examined because of a history of lethargy and vomiting. Histology, immunohistochemistry, and polymerase chain reaction (PCR) examination of a hepatic mass confirmed the presence of an alveolar hydatid cyst, the first description of Echinococcus multilocularis in British Columbia. We provide recommendations for case management and remind practitioners in endemic areas of western Canada that dogs can serve as definitive and, rarely, intermediate hosts for E. multilocularis.

Comment on “Effects of Arsenite during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Diseases in Male Mice” and “Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Trends and Scientific Gaps”

Peer reviewed

Reduced Insulin Clearance And Lower Insulin-degrading Enzyme Expression In The Liver Might Contribute To The Thrifty Phenotype Of Protein-restricted Mice.

Nutrient restriction during the early stages of life usually leads to alterations in glucose homeostasis, mainly insulin secretion and sensitivity, increasing the risk of metabolic disorders in adulthood. Despite growing evidence regarding the importance of insulin clearance during glucose homeostasis in health and disease, no information exists about this process in malnourished animals. Thus, in the present study, we aimed to determine the effect of a nutrient-restricted diet on insulin clearance using a model in which 30-d-old C57BL/6 mice were exposed to a protein-restricted diet for 14 weeks. After this period, we evaluated many metabolic variables and extracted pancreatic islet, liver, gastrocnemius muscle (GCK) and white adipose tissue samples from the control (normal-protein diet) and restricted (low-protein diet, LP) mice. Insulin concentrations were determined using RIA and protein expression and phosphorylation by Western blot analysis. The LP mice exhibited lower body weight, glycaemia, and insulinaemia, increased glucose tolerance and altered insulin dynamics after the glucose challenge. The improved glucose tolerance could partially be explained by an increase in insulin sensitivity through the phosphorylation of the insulin receptor/protein kinase B and AMP-activated protein kinase/acetyl-CoA carboxylase in the liver, whereas the changes in insulin dynamics could be attributed to reduced insulin secretion coupled with reduced insulin clearance and lower insulin-degrading enzyme (IDE) expression in the liver and GCK. In summary, protein-restricted mice not only produce and secrete less insulin, but also remove and degrade less insulin. This phenomenon has the double benefit of sparing insulin while prolonging and potentiating its effects, probably due to the lower expression of IDE in the liver, possibly with long-term consequences.

Human Herpesvirus-6 And Cytomegalovirus Dna In Liver Donor Biopsies And Their Correlation With Hla Matches And Acute Cellular Rejection.

Herpesvirus reactivation is common after liver transplantation. Analyze the presence of cytomegalovirus (HCMV) and human herpesvirus-6 (HHV-6) DNA in liver donor biopsies, seeking to better understand issues involving human donor leukocyte antigens (HLA)-A, B and DR, as well as correlations with acute cellular rejection. Fifty-nine liver transplantation patients were investigated for the presence of HCMV and HHV-6 DNA in liver donor biopsies, using the Nested-PCR technique. The clinical donor information and HLA matches were obtained from the São Paulo State Transplant System. The recipients' records regarding acute cellular rejection were studied. Seven (11.8%) biopsies were positive for HCMV DNA and 29 (49%) were positive for HHV-6 DNA. In 14 donors with HLA-DR 15 nine had HHV-6 DNA positive liver biopsy with a tendency for significant association (p=0.09), 22 recipients developed acute cellular rejection and 9/22 were positive for HLA-DR 15 (p=0.03; χ(2)=4.51), which was statistically significant in univariate analysis and showed a tendency after multivariate analysis (p=0.08). HHV-6 DNA was prevalent in liver donors studied as well as HLA-DR 15. These findings suggest that patients with HLA-DR 15 in liver donor biopsies develop more rejection after liver transplantation.

Differential regulation of PGC-1 alpha expression in rat liver and skeletal muscle in response to voluntary running

Background: The beneficial actions of exercise training on lipid, glucose and energy metabolism and insulin sensitivity appear to be in part mediated by PGC-1 alpha. Previous studies have shown that spontaneously exercised rats show at rest enhanced responsiveness to exogenous insulin, lower plasma insulin levels and increased skeletal muscle insulin sensitivity. This study was initiated to examine the functional interaction between exercise-induced modulation of skeletal muscle and liver PGC-1 alpha protein expression, whole body insulin sensitivity, and circulating FFA levels as a measure of whole body fatty acid (lipid) metabolism. Methods: Two groups of male Wistar rats (2 Mo of age, 188.82 +/- 2.77 g BW) were used in this study. One group consisted of control rats placed in standard laboratory cages. Exercising rats were housed individually in cages equipped with running wheels and allowed to run at their own pace for 5 weeks. At the end of exercise training, insulin sensitivity was evaluated by comparing steady-state plasma glucose (SSPG) concentrations at constant plasma insulin levels attained during the continuous infusion of glucose and insulin to each experimental group. Subsequently, soleus and plantaris muscle and liver samples were collected and quantified for PGC-1 alpha protein expression by Western blotting. Collected blood samples were analyzed for glucose, insulin and FFA concentrations. Results: Rats housed in the exercise wheel cages demonstrated almost linear increases in running activity with advancing time reaching to maximum value around 4 weeks. On an average, the rats ran a mean (Mean +/- SE) of 4.102 +/- 0.747 km/day and consumed significantly more food as compared to sedentary controls (P < 0.001) in order to meet their increased caloric requirement. Mean plasma insulin (P < 0.001) and FFA (P < 0.006) concentrations were lower in the exercise-trained rats as compared to sedentary controls. Mean steady state plasma insulin (SSPI) and glucose (SSPG) concentrations were not significantly different in sedentary control rats as compared to exercise-trained animals. Plantaris PGC-1 alpha protein expression increased significantly from a 1.11 +/- 0.12 in the sedentary rats to 1.74 +/- 0.09 in exercising rats (P < 0.001). However, exercise had no effect on PGC-1 alpha protein content in either soleus muscle or liver tissue. These results indicate that exercise training selectively up regulates the PGC-1 alpha protein expression in high-oxidative fast skeletal muscle type such as plantaris muscle. Conclusion: These data suggest that PGC-1 alpha most likely plays a restricted role in exercise-mediated improvements in insulin resistance (sensitivity) and lowering of circulating FFA levels.

A novel mutation in the glycogen synthase 2 gene in a child with glycogen storage disease type 0

Background: Glycogen storage disease type 0 is an autosomal recessive disease presenting in infancy or early childhood and characterized by ketotic hypoglycemia after prolonged fasting and postprandial hyperglycemia and hyperlactatemia. Sixteen different mutations have been identified to date in the gene which encodes hepatic glycogen synthase, resulting in reduction of glycogen storage in the liver. Case Presentation: Biochemical evaluation as well as direct sequencing of exons and exon-intron boundary regions of the GYS2 gene were performed in a patient presenting fasting hypoglycemia and postprandial hyperglycemia and her parents. The patient was found to be compound heterozygous for one previously reported nonsense mutation (c. 736 C>T; R243X) and a novel frameshift mutation (966_967delGA/insC) which introduces a stop codon 21 aminoacids downstream from the site of the mutation that presumably leads to loss of 51% of the COOH-terminal part of the protein. The glycemia and lactatemia of the parents after an oral glucose tolerance test were evaluated to investigate a possible impact of the carrier status on the metabolic profile. The mother, who presented a positive family history of type 2 diabetes, was classified as glucose intolerant and the father, who did not exhibit metabolic changes after the glucose overload, had an antecedent history of hypoglycemia after moderate alcohol ingestion. Conclusion: The current results expand the spectrum of known mutations in GYS2 and suggest that haploinsufficiency could explain metabolic abnormalities in heterozygous carriers in presence of predisposing conditions.

Prognostic factors for progression of liver structural lesions in chronic hepatitis C patients

AIM: To evaluate the epidemiological, clinical, laboratory and histological variables capable of predicting the progression of hepatic structural disturbances in chronic hepatitis C patients during the time interval between two liver biopsies. METHODS: Clinical charts of 112 chronic hepatitis C patients were retrospectively analyzed, whereas liver biopsies were revised. Immunohistochemical detection of interferon receptor was based on the Envision-Peroxidase System. RESULTS: In the multivariate analysis, the variables in the age at first biopsy, ALT levels, presence of lymphoid aggregates and siderosis were the determinants of the best model for predicting the severity of the disease. The direct progression rate of hepatic structural lesions was significantly higher in untreated patients, intermediate in treated non-responders and lower in treated responders to antiviral therapy (non-treated vs responders, 0.22 +/- 0.50 vs -0.15 +/- 0.46, P = 0.0053). Immuno-expression of interferon receptor is not a relevant factor. CONCLUSION: The best predictors of the progression of fibrosis are age at the first liver biopsy, extent of ALT elevation, inflammation at liver histology and hepatic siderosis. Antiviral treatment is effective in preventing the progression of liver structural lesions in chronic hepatitis C patients. (C) 2008 WJG. All rights reserved.

Does bilioenteric anastomosis impair results of liver resection in primary intrahepatic lithiasis?

AIM: To evaluate the long-term results of liver resection for the treatment of primary intrahepatic lithiasis. Prognostic factors, especially the impact of bilioenteric anastomosis on recurrence of symptoms were assessed. METHODS: Forty one patients with intrahepatic stones and parenchyma fibrosis/atrophy and/or biliary stenosis were submitted to liver resection. Resection was associated with a Roux-en-Y hepaticojejunostomy in all patients with bilateral stones and in those with unilateral disease and dilation of the extrahepatic biliary duct (> 2 cm). Late results and risk factors for recurrence of symptoms or stones were evaluated. RESULTS: There was no operative mortality. After a mean follow-up of 50.3 mo, good late results were observed in 82.9% of patients; all patients submitted to liver resection alone and 58.8% of those submitted to liver resection and hepaticojejunostomy were free of symptoms (P = 0.0006). Patients with unilateral and bilateral disease showed good late results in 94.1% and 28.6%, respectively (P < 0.001). CONCLUSION: Recurrence of symptoms in patients with hepaticojejunostomy showed that this may not be the ideal solution. Further studies are needed to establish the best treatment for patients with bilateral stones or unilateral disease and a dilated extrahepatic duct. (C) 2010 Baishideng. All rights reserved.