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Effective noninvasive tests that can distinguish early-stage nonalcoholic steatohepatitis (NASH) from simple steatosis (SS) have long been sought. Our aim was to determine the possibility of noninvasively distinguishing early-stage NASH from SS.We used Fick's principle and the Kety-Schmidt equation to determine the hepatic tissue blood flow (TBF) in 65 NASH patients who underwent xenon computed tomography (Xe-CT). We calculated the lambda value (LV), i.e., Xe gas solubility coefficient, in liver and blood. We assessed the histological severity of fatty changes and fibrosis on the basis of Brunt's classification. Liver biopsy revealed SS in 9 patients and NASH in 56 patients. NASH stages 1 and 2 were classified as early-stage NASH (Ea-NASH; 38 patients) and stages 3 and 4 as advanced-stage NASH (Ad-NASH; 18 patients). We evaluated the differences in LV and TBF among the 3 groups.LV was significantly lower in the Ad-NASH group than in the SS and Ea-NASH groups. Portal venous TBF (PVTBF) was significantly lower in the Ea-NASH group than in the SS group, and PVTBF was lower in the Ad-NASH group than in the Ea-NASH group. Total hepatic TBF (THTBF) was significantly different between the SS and Ea-NASH groups and between the SS and Ad-NASH groups.In conclusion, measurements of TBF and LV are useful for evaluating the pathophysiological progression of NASH. In addition, these measurements can facilitate the differential diagnosis of SS and Ea-NASH, which may not be distinguishable by other means.

Strategies for improving the viability of steatotic donor livers could increase the number of organs suitable for transplantation. There is evidence that adiponectin, the most abundant adipose-specific adipokine, acts as an anti-obesity and anti-inflammatory hormone. Here we review the signaling pathways of adiponectin and the possible therapies based on adiponectin regulation that have been examined or applied clinically. Recent studies on the role of adiponectin in steatotic livers subjected to ischemia/reperfusion are discussed. The data suggest that further investigations are required to determine whether adiponectin is a potential therapeutic target in liver transplantation. Liver Transpl 17:993–1004, 2011. © 2011 AASLD.

With the continuing epidemics of obesity and diabetes, nonalcoholic fatty liver disease (NAFLD) has received increased attention. Great efforts are being undertaken to improve the noninvasive diagnosis of NAFLD, with the ultimate goal of optimizing treatment options and clinical outcomes. Research suggests that blood-borne biochemical markers can be used to distinguish simple steatosis from nonalcoholic steatohepatitis (NASH), thus reducing the need of liver biopsy. Future developments in the field of diagnostic biochemistry within the spectrum of NAFLD can make this approach ideal for screening and monitoring purposes. In this review, we provide an overview of the different blood-borne markers which have been recently proposed for differentiating simple steatosis from NASH. We will also consider the practical and statistical issues that seem to be limiting the effective integration of biomarkers into clinical development.

Steatotic liver grafts represent the most common type of “extended criteria” organs that have been introduced during the last two decades due to the disparity between liver transplant candidates and the number available organs. A precise definition and reliable and reproducible method for steatosis quantification is currently lacking and the potential influence of the chemical composition of hepatic lipids has not been addressed. In our view, these shortcomings appear to contribute significantly to the inconsistent results of studies reporting on graft steatosis and the outcome of liver transplantation. In this review, various definitions, prevalence and methods of quantification of liver steatosis will be covered. Ischemia/reperfusion injury of the steatotic liver and its consequences on post-transplant outcome will be discussed. Selection criteria for organ allocation and a number of emerging protective strategies are suggested.

Aim To compare ultrasound gradings of steatosis with fat fraction (FF) on magnetic resonance spectroscopy (MRS; the non-invasive reference standard for quantification of hepatic steatosis), and evaluate inter- and intraobserver variability in the ultrasound gradings. Materials and methods Triple grading of hepatic ultrasound examination was performed by three independent graders on 131 people with type 2 diabetes. The stored images of 60 of these individuals were assessed twice by each grader on separate occasions. Fifty-eight patients were pre-selected on the basis of ultrasound grading (normal, indeterminate/mild steatosis, or severe steatosis) to undergo 1 H-MRS. The sensitivity and specificity of the ultrasound gradings were determined with reference to MRS data, using two cut-offs of FF to define steatosis, ≥9% and ≥6.1%. Results Median (intraquartile range) MRS FF (%) in the participants graded on ultrasound as normal, indeterminate/mild steatosis, and severe steatosis were 4.2 (1.2–5.7), 4.1 (3.1–8.5) and 19.4 (12.9–27.5), respectively. Using a liver FF of ≥6.1% on MRS to denote hepatic steatosis, the unadjusted sensitivity and specificity of ultrasound gradings (severe versus other grades of steatosis) were 71 and 100%, respectively. Interobserver agreement within one grade was observed in 79% of cases. Exact intraobserver agreement ranged from 62 to 87%. Conclusion Hepatic ultrasound provided a good measure of the presence of significant hepatic steatosis with good intra- and interobserver agreement. The grading of a mildly steatotic liver was less secure and, in particular, there was considerable overlap in hepatic FF with those who had a normal liver on ultrasound.

Objective: To evaluate the performance of a diagnostic model based on a composite index using clinical and laboratory data, including cardiovascular biomarkers, to help practitioners to differentiate patients with simple steatosis from those with nonalcoholic steatohepatitis (NASH). Design and methods: 101 patients with biopsy proven features of nonalcoholic fatty liver disease were included. We investigated the usefulness of 9 biomarkers in predicting the histological disease severity, including routine biochemical tests, C-reactive protein, soluble intercellular adhesion molecule-1 (sICAM-1) and anthropometric evaluation. Receiver operating characteristic (ROC) curves and likelihood ratios (LRs) were used to evaluate the fit of each test. A composite index was calculated as the product of each individual test LR. Results: In a model patient who has all positive tests, the post-test probability for NASH would be 99.5%. Conclusion: The capacity of each individual biomarker to independently predict the disease outcome was lower than a composite index constructed after multiplying the LR for each individual test combined into a “multimarker” score. Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Castaño, Gustavo Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentina Fil: Burgueño, Adriana Laura. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Fernández Gianotti, Tomás. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Rosselli, Maria Soledad. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pirola, Carlos José. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Objectives: Reduced vitamin E levels have been reported in patients with non-alcoholic steatohepatitis (NASH), but no conclusive data on patients with simple steatosis (SS) are available. Aim of this study was to investigate the association between serum vitamin E levels and SS. Methods: A cohort of 312 patients with cardio-metabolic risk factors was screened for liver steatosis by ultrasonography (US). We reasonably classified as SS patients with US-fatty liver, normal liver function tests (LFTs) and with Cytokeratin 18 6 months). Serum cholesterol-adjusted vitamin E (Vit E/chol) levels were measured. Results: Mean age was 53.9±12.5 years and 38.4% were women. Non-alcoholic fatty liver disease (NAFLD) was detected at US in 244 patients; of those 39 had biopsy-proven NASH and 2 borderline NASH. Vit E/chol was reduced in both SS (3.4±2.0, P

Steatotic liver grafts are associated with a high incidence of primary nonfunction and initial poor function. Due to the increasing number of liver transplant candidates, centers are inclined to accept marginal donors more frequently. For a lack of a reliable fatty liver model, preservation concepts for fatty livers have hardly been evaluated. Moreover, there is an ongoing debate on the relevance and impact of micro- versus macrovesicular steatotic organs. We therefore intended to establish a steatotic liver model in pigs comprising both micro- and macrovesicular steatotic livers. Five groups of pigs received daily 1 to 6 g ethanol/kg body weight and/or a protein-deficient diet for up to 72 days. Liver biopsy was carried out at days 24, 48, and 72. With an increasing amount and duration of ethanol intake, higher levels of microvesicular steatosis were induced. Ethanol and protein deficient diet resulted in more than 60% microvesicular steatosis after 72 days. Exclusively protein-deficient diet without ethanol induced macrovesicular steatosis of more than 70% after 72 days. For the first time, we established a porcine model of hepatic steatosis that comprises both histologic types of fatty liver: micro- and macrovesicular steatosis induced by ethanol and a protein-deficient diet. We would like to conclude that our model is particularly qualified to study new concepts of preservation for steatotic livers to improve on the posttransplant outcome.

INTRODUCTION: Nearly 22 million people suffer from heart failure (HF) worldwide. Heart transplantation is the only viable treatment option, but donor organ shortage and immunosuppression remain significant challenges. The creation of a bioartificial heart could overcome limitations. In this work, we recellularized human heart matrix slices with human induced pluripotent stem (iPS) derived cardiomyocytes to create contracting human myocardium.

We were most interested to read the recent report by Serviddio and colleagues ( Gut 2008; 57 :957–65). This work not only showed that upregulation of uncoupling protein-2 was a reason for progression of non-alcoholic steatohepatitis (NASH) from simple steatosis, but also gave an explanation for why NASH liver was especially vulnerable to ischaemia–reperfusion injury. NASH is a common liver disease that is estimated to affect nearly 1% of the population. A growing body of evidences shows that NASH …

The decreased tolerance of steatotic livers to warm ischemia complicates liver surgery. The efficacy of heat shock preconditioning in steatotic livers to lessen ischemia-reperfusion injury was studied in rats. Steatotic liver was produced in Lewis rats with a choline-deficient diet. Rats with steatotic livers were divided into a heat shock preconditioned group (group HS) and a control group (group C). All rats received 45 min of hepatic warm ischemia. Survival rates and changes in biochemical and histological parameters were compared in both groups. Heat shock protein 72 (HSP72) was produced only in group HS. The 7-day survival of the rats after warm ischemic intervention was significantly better in group HS (13/15) than in group C (5/15) (P0.01). The concentration of ATP in liver tissue (n = 10, P0.01) and serum levels of aspartate aminotransferase (n = 10, P0.05), alanine aminotransferase (n = 10, P0.01), and lactic dehydrogenase (n = 10, P0.01) at 40 min reperfusion were also significantly better in group HS than in group C. Histological examination at 40 min reperfusion showed severe sinusoidal congestion, hepatocyte necrosis, and increased positivity to 4-hydroxy-2-nonenal-modified proteins in group C livers; these signs were markedly suppressed in group HS livers. The data indicate that heat shock preconditioning provides the steatotic rat liver with significant tolerance to warm ischemia-reperfusion injury.

a Department of Internal Medicine I, Regensburg University Hospital, D-93042 Regensburg, Germany b Center for Liver Cell Research and Department of Pediatrics, Regensburg University Hospital, D-93042 Regensburg, Germany c Department of Surgery, Regensburg University Hospital, D-93042 Regensburg, Germany d Institute for Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, D-93042 Regensburg, Germany

Clinical experience suggests that grafts obtained from steatotic livers result in primary nonfunction more frequently than those from nonsteatotic livers. To date, however, only a few studies have been done to verify the accuracy of this observation. To investigate the effects of cold preservation on steatotic liver viability, liver grafts obtained from rats fed with a choline-deficient diet were transplanted after periods of cold preservation. Recipient survival rates with normal liver grafts were 8/8 (100%) and those with steatotic liver grafts were 7/8 (88%) (P > 0.05) after 1-hr preservation with UW solution. After 9-hr preservation, however, these rates decreased significantly to 0/8 (0%) with steatotic grafts (P < 0.01), but were not significantly decreased with normal grafts. LDH levels in the effluent at the time of transplantation were 133 IU/L (1-hr) and 512 IU/L (9-hr) in normal livers, but in steatotic livers these were elevated to 598 and 3141 IU/L, respectively (P < 0.01). Recovery rates of hepatic blood flow measured by laser Doppler flowmeter after revascularization were 99% (1-hr) and 96% (9-hr) in normal grafts, but in steatotic grafts they were 98% (1-hr) and 63% (9-hr, P < 0.01). In addition, the oxidative phosphorylation ability of liver mitochondria obtained from steatotic grafts was decreased significantly after cold preservation. The present results suggest that steatotic liver grafts are prone to lose their viability more easily than normal liver grafts after prolonged periods of cold preservation due to a combination of causes.

To investigate whether serum levels of two soluble forms of extracellular cytokeratin 18 (M30-antigen and M65-antigen) may differentiate nonalcoholic steatohepatitis (NASH) from simple steatosis in patients with nonalcoholic fatty liver disease (NAFLD).A total of 83 patients with suspected NAFLD and 49 healthy volunteers were investigated. Patients with suspected NAFLD were classified according to their liver histology into four groups: definitive NASH (n=45), borderline NASH (n=24), simple fatty liver (n=9), and normal tissue (n=5). Serum levels of caspase-3 generated cytokeratin-18 fragments (M30-antigen) and total cytokeratin-18 (M65-antigen) were determined by ELISA.Levels of M30-antigen and M65-antigen were significantly higher in patients with definitive NASH compared to the other groups. An abnormal value (121.60 IU/L) of M30-antigen yielded a 60.0% sensitivity and a 97.4% specificity for the diagnosis of NASH. Sensitivity and specificity of an abnormal M65-antigen level (243.82 IU/L) for the diagnosis of NASH were 68.9% and 81.6%, respectively. Among patients with NAFLD, M30-antigen and M65-antigen levels distinguished between advanced fibrosis and early-stage fibrosis with a sensitivity of 64.7% and 70.6%, and a specificity of 77.3% and 71.2%, respectively.Serum levels of M30-antigen and M65-antigen may be of clinical usefulness to identify patients with NASH. Further studies are mandatory to better assess the role of these apoptonecrotic biomarkers in NAFLD pathophysiology.

We here describe the morphologies of 9 macroregenerative nodules (MRNs) showing moderate to marked fatty change (fatty MRN) from 6 cases of non- or minimally-steatotic cirrhotic livers. In most of these cases, no obvious steatogenic factors of the liver were obtainable. These fatty MRNs showed more or less a sharp border. Seven of these fatty MRNs showed a variable degree of unusual morphological alterations suggestive of neoplasia: atypical and hyperchromatic nuclei, abnormal blood vessels, foci of clustering Mallory bodies, numerous hyaline globules, alpha-fetoprotein-positive hepatocytes, resistance to iron accumulation, infiltration into the portal tracts within MRN, and occurrence of hepatocellular carcinoma without fatty change. These observations suggest that at least some of the fatty MRNs are neoplastic or belong to a borderline lesion, and that the fatty change in the MRNs may be one of hepatocellular expressions related to human hepatocarcinogenesis.