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PURPOSE Over the last two decades, extended criteria have promoted an increased number of donor livers available for liver transplantation. But posttransplant graft loss is still a major concern. Macrovesicular hepatic steatosis (MHS) is recognized as the most significant prognostic histologic parameter in predicting posttransplant graft loss. We aimed to evaluate the utility of ex vivo volumetric quantitative MRI for quantifying MHS before liver transplantation using proton density fat-fraction (PDFF-MRI) histogram analysis. METHODS PDFF-MRI was performed at 3.0T in 40 livers. We obtained histogram parameters of whole-liver volume of interest, including the mean, median, 5th, 10th, 25th, 75th, 90th, and 95th percentile PDFF; skewness; kurtosis; entropy; and volume. RESULTS Livers from 40 cadaveric donors were included, and histologic ex vivo fat quantification was available for 33 livers. Ten livers had MHS and 23 had normal fat content. The MHS group had higher mean, median, 5th, 10th, 25th, 75th, 90th, and 95th percentile PDFF, and entropy than the group with normal fat content (P < .05). Median PDFF had greater area under the curve value than other parameters. Mean PDFF showed an excellent correlation with entropy and a moderate correlation with MHS quantification on histology. CONCLUSIONS Ex vivo volumetric quantitative PDFF-MRI histogram analysis is a very useful and noninvasive method to detect MHS before liver transplantation. Median PDFF was the best predictor of the presence of MHS. Entropy is a very promising parameter.

Background: Hepatic steatosis and chemotherapy in the treatment of colorectal liver metastases (CLM) are often linked to increased mortality and morbidity after liver resection. This study evaluates the influence of macrovesicular hepatic steatosis and chemotherapeutic regimes on graded morbidity and mortality after liver resection for CLM. Methods: A total of 323 cases of liver resection for CLM were retrospectively analysed using univariable and multivariable linear, ordinal and Cox regression analyses. The resected liver tissue was re-evaluated by a single observer to determine the grade and type of hepatic steatosis. Results: Macrovesicular steatosis did not influence postoperative morbidity and survival, as evidenced by risk-adjusted multivariable Cox regression analysis (p = 0.521). Conversion chemotherapy containing oxaliplatin was an independent and significant risk factor for mortality in risk-adjusted multivariable Cox regression analysis (p = 0.005). Identified independently, significant risk factors for postoperative morbidity were neoadjuvant treatment of metastases of the primary tumour with irinotecan (p = 0.003), the duration of surgery in minutes (p = 0.001) and the number of intraoperatively transfused packed red blood cells (p ≤ 0.001). Surprisingly, macrovesicular hepatic steatosis was not a risk factor for postoperative morbidity and was even associated with lower rates of complications (p = 0.006). Conclusion: The results emphasize the multifactorial influence of preoperative liver damage and chemotherapy on the severity of postoperative morbidity, as well as the significant impact of conversion chemotherapy containing oxaliplatin on survival.

Although several non-alcoholic steatohepatitis (NASH) models have been reported to date, few of these models fully reflect the histopathology and pathophysiology of human NASH. The aim of this study was to establish a novel NASH model by feeding a high-fat (HF) diet and administering both carbon tetrachloride (CCl4 ) and the Liver X receptor agonist T0901317. Male C57BL/6J mice were divided into four groups (each n = 5): HF, HF + CCl4 , HF + T0901317, and the novel NASH model (HF + CCl4 + T0901317). CCl4 (0.1 mL/kg) and T0901317 (2.5 mg/kg) were intraperitoneally administered four times and five times, respectively. The livers of the novel NASH model group presented a whitish colour. The serum levels of TNF-α and IL-6 were significantly increased in the novel NASH model group, and mice in this group exhibited histopathological features and insulin resistance reflective of NASH, i.e., macrovesicular hepatic steatosis, ballooning hepatocytes, Mallory-Denk bodies, lobular inflammation and fibrosis. The novel NASH model group presented significantly upregulated expression levels of mRNAs related to lipogenesis, oxidative stress, fibrosis and steatosis and significantly downregulated expression levels of mRNAs related to triglyceride export. We successfully established a novel experimental NASH model that exhibits similar histopathology and pathophysiology to human NASH.

The accumulation of excess fat in the liver (hepatic steatosis) in the absence of heavy alcohol consumption causes nonalcoholic fatty liver disease (NAFLD), which has become a global epidemic. Identifying metabolic risk factors that interact with the genetic risk of NAFLD is important for reducing disease burden. We tested whether serum glucose, insulin, insulin resistance, triglyceride (TG), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, body mass index (BMI), and waist-to-hip ratio adjusted for BMI interact with genetic variants in or near the patatin-like phospholipase domain containing 3 (PNPLA3) gene, the glucokinase regulatory protein (GCKR) gene, the neurocan/transmembrane 6 superfamily member 2 (NCAN/TM6SF2) gene, and the lysophospholipase-like 1 (LYPLAL1) gene to exacerbate hepatic steatosis, estimated by liver attenuation. We performed association analyses in 10 population-based cohorts separately and then meta-analyzed results in up to 14,751 individuals (11,870 of European ancestry and 2,881 of African ancestry). We found that PNPLA3-rs738409 significantly interacted with insulin, insulin resistance, BMI, glucose, and TG to increase hepatic steatosis in nondiabetic individuals carrying the G allele. Additionally, GCKR-rs780094 significantly interacted with insulin, insulin resistance, and TG. Conditional analyses using the two largest European ancestry cohorts in the study showed that insulin levels accounted for most of the interaction of PNPLA3-rs738409 with BMI, glucose, and TG in nondiabetic individuals. Insulin, PNPLA3-rs738409, and their interaction accounted for at least 8% of the variance in hepatic steatosis in these two cohorts. Conclusion: Insulin resistance, either directly or through the resultant elevated insulin levels, more than other metabolic traits, appears to amplify the PNPLA3-rs738409-G genetic risk for hepatic steatosis. Improving insulin resistance in nondiabetic individuals carrying PNPLA3-rs738409-G may preferentially decrease hepatic steatosis.

Background.Nonalcoholic fatty liver disease (NAFLD) is one of the complications of the metabolic syndrome. It encompasses a wide range of disease spectrum from simple steatosis to liver cirrhosis. Structural alteration of hepatic mitochondria might be involved in the pathogenesis of NAFLD.Aims.In the present study, we used a newly established model of fructose-induced metabolic syndrome in male Wistar rats in order to investigate the ultrastructural changes in hepatic mitochondria that occur with fructose consumption and their association with NAFLD pathogenesis.Methods.The concentration of fructose-drinking water (FDW) used in this study was 20%. Six male Wistar rats were supplemented with FDW 20% for eight weeks. Body composition and metabolic parameters were measured before and after 8 weeks of FDW 20%. Histomorphology of the liver was evaluated and ultrastructural changes of mitochondria were assessed with transmission electron micrograph.Results.After 8 weeks of fructose consumption, the animals developed several features of the metabolic syndrome. Moreover, fructose consumption led to the development of macrovesicular hepatic steatosis and mitochondrial ultrastructural changes, such as increase in mitochondrial size, disruption of the cristae, and reduction of matrix density.Conclusion.We conclude that in male Wistar rat 8-week consumption of FDW 20% leads to NAFLD likely via mitochondrial structural alteration.

To evaluate the diagnostic performance of both breath-hold T2*-corrected triple-echo spoiled gradient-echo water-fat separation magnetic resonance (MR) imaging (triple-echo imaging) and high-speed T2-corrected multiecho hydrogen 1 ((1)H) MR spectroscopy in the assessment of macrovesicular hepatic steatosis in living liver donor candidates by using histologic assessment as a reference standard.The institutional review board approved this retrospective study with waiver of the need to obtain informed consent. One hundred eighty-two liver donor candidates who had undergone preoperative triple-echo imaging and single-voxel (3 × 3 × 3 cm) MR spectroscopy performed with a 3.0-T imaging unit and who had also undergone histologic evaluation of macrovesicular steatosis were included in this study. In part 1 of the study (n = 84), the Pearson correlation coefficient was calculated. Receiver operating characteristic (ROC) curve analysis was performed to detect substantial (≥10%) macrovesicular steatosis. In part 2 of the study, with a different patient group (n = 98), diagnostic performance was evaluated by using the diagnostic cutoff values determined in part 1 of the study.The correlation coefficients of triple-echo MR imaging and MR spectroscopy with macrovesicular steatosis were 0.886 and 0.887, respectively. The areas under the ROC curve for detection of substantial macrovesicular steatosis were 0.959 and 0.988, with cutoff values of 4.93% and 5.79%, respectively, and without a significant difference (P = .328). In the part 2 study group, sensitivity and specificity were 90.9% (10 of 11) and 86.2% (75 of 87) for triple-echo MR imaging and 90.9% (10 of 11) and 86.2% (75 of 87) for MR spectroscopy, respectively.Either breath-hold triple-echo MR imaging or MR spectroscopy can be used to detect substantial macrovesicular steatosis in living liver donor candidates. In the future, this may allow selective biopsy in candidates who are expected to have substantial macrovesicular steatosis on the basis of MR-based hepatic fat fraction.

Non-alcoholic fatty liver disease (NAFLD) is worldwide epidemic. This clinical entity is closely related to metabolic syndrome. Majority of the patients are obese. Metabolic factors and genetics play important roles in the pathogenesis of this disorder. NAFLD encompasses a spectrum of disorders including benign macrovesicular hepatic steatosis, non-alcoholic steatohepatitis, fibrosis, hepatic cirrhosis and hepatocellular carcinoma. Is expected that it is became the most common indication of liver transplantation in a few years. It is diagnosed by abnormal liver biochemistry, imaging methods and liver biopsy. Several therapeutic agents were investigated for optimal management of this disease, however, at the present, there are limited treatment options which include lifestyle modification to loss of body weight, vitamin E and thioglitazones.

Background/Aims Ultrasound is used to screen for hepatic steatosis, the most common liver disease in the United States. However, few studies have prospectively evaluated the accuracy of ultrasound to diagnose hepatic steatosis. Therefore, a double blinded prospective study was performed in consecutive patients undergoing liver biopsy to evaluate the accuracy of ultrasound to diagnose hepatic steatosis. Methods Real time ultrasound was performed just prior to the biopsy by a single investigator masked to the clinical diagnosis. The liver biopsy was reviewed by a pathologist masked to the clinical indication or sonographic findings. Results Of 73 consecutive patients studied, macrovesicular steatosis of any severity on biopsy was found in 46 (63%) and micro vesicular fat found in 51 (69.9%). The overall impression of the sonographer for the presence of macrovesicular hepatic steatosis of any degree had a sensitivity of 60.9% and a specificity of 100%. The sensitivity increased to 100% and the specificity to 90% when there was⩾20% of fat. The zonular distribution of the fat did not alter the diagnostic accuracy of ultrasound. Ultrasound had a poor yield in the diagnosis of microvesicular fat with an overall sensitivity of 43% and a specificity of 73%. The combination of increased echogenicity and portal vein blurring on ultrasound had the greatest sensitivity in the diagnosis of hepatic steatosis. Conclusion Real time ultrasound using a combination of sonographic findings has a high specificity but underestimates the prevalence of hepatic steatosis when there is

Background. In liver transplantation, macrovesicular steatosis is a major determinant of graft outcome. Visual assessment of steatosis by the donor surgeon is highly inaccurate, whereas hepatic biopsy is user dependent and cumbersome. Our objective was to validate a novel bioelectrical impedance sensor as a means of objectively quantifying macrovesicular hepatic steatosis and to correlate the results with another surrogate measure of macrosteatosis, hepatic microcirculation. Methods. Fatty (n=36) and lean (n=18) male Zucker rats, 250 to 450 g, were used to achieve varying degrees of steatosis. After a bilateral subcostal incision, hepatic microcirculation was measured using laser Doppler microflowmetry. Low-frequency bioelectrical impedance (LF-BEI) was measured at 1 kHz using a custom-made sensor and instrumentation system. Complete hepatectomy was performed. Hepatic tissue was preserved and stained with hematoxylin-eosin for histology. Results and Conclusion. Both microflow and LF-BEI correlated well with macrosteatosis and each other: Pearson correlation coefficients −0.71, 0.73, and −0.81, respectively. Livers were grouped according to the degree of macrosteatosis: mild ( 60%). Both LF-BEI and microflow varied significantly among groups on one-way analysis of variance, although only LF-BEI was capable of discriminating between mild and moderate macrosteatosis on post hoc analysis. Regarding their individual capacities to detect the presence of severe macrosteatosis, both tests were excellent classifiers: receiver operating curve area under the curve 0.885 and 0.9 for LF-BEI and microflow, respectively. However, the bioimpedance apparatus is more rapid and less susceptible to local factors and background noise and could more easily be used in the clinical liver transplantation setting.

To evaluate the diagnostic performance of magnetic resonance (MR) fat quantification and MR elastography for the assessment of hepatic steatosis and fibrosis in living liver donor candidates.This retrospective study was approved by the institutional review board, and the requirement of informed consent was waived. Donors who underwent MR fat quantification and MR elastography at 1.5 T, followed by liver biopsy, were chronologically grouped into test and validation groups. In the test group (n = 362), MR fat fraction and liver stiffness were compared among donors with normal parenchyma (n = 244), simple steatosis (n = 71), steatosis with inflammatory activity (n = 21), nonalcoholic steatohepatitis (n = 17), and fibrosis (n = 9). Diagnostic performance of the two techniques was assessed by using receiver operating characteristic curve analysis for the detection of substantial steatosis (macrovesicular fat ≥ 10%) or fibrosis (≥F1) and was tested in a validation group (n = 34).In the test group, donors with steatosis showed significantly higher fat fraction than donors without steatosis (P.0001), and donors with fibrosis and nonalcoholic steatohepatitis showed significantly higher liver stiffness values than donors without fibrosis (P.0001). Areas under the curve were 0.93 (cutoff value5.8%) for MR fat quantification and 0.85 (cutoff value1.94 kPa) for MR elastography. By using those values, the combination of the two techniques could be used to detect substantial steatosis or fibrosis with 100% sensitivity (12 of 12 patients, 95% confidence interval: 73.4%, 100%) and 100% negative predictive value (15 of 15 patients, 95% confidence interval: 78.0%, 100%) in the validation group.A combination of MR fat quantification and MR elastography can provide sufficient sensitivity to detect substantial steatosis or fibrosis (≥F1) in liver donor candidates.

L-Asparaginase is commonly used in combination chemotherapy of both pediatric and adult acute lymphoblastic leukemia. The majority of adverse effects are hypersensitivity reactions, but serious liver injury may also occur. It has been shown that treatment with L-asparaginase can be associated mainly with macrovesicular hepatic steatosis which may be accompanied by alterations in lipid metabolism. So far, the mechanism for liver injury associated with L-asparaginase is not known. We report here an adult patient who developed mixed liver injury and predominantly microvesicular hepatic steatosis while being treated with L-asparaginase for acute lymphoblastic leukemia. The patient developed liver failure and died due to multiorgan failure. Both impaired liver mitochondrial function and alterations in very-low-density lipoprotein metabolism and secretion are discussed as two possible mechanisms explaining the findings observed in this patient.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in children aged 2 to 19 years. It is defined as excessive deposition of fat in the liver leading to macrovesicular hepatic steatosis. This disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) with active inflammation and finally to end-stage cirrhosis. The major risk factor for NAFLD in children is obesity. The prevalence of NAFLD in these children is estimated to be between 8% and 23% in the United States. These wide discrepancies in prevalence rates are due to utilization of varying diagnostic criteria, including the absence of histopathological evidence, which is still considered the gold standard in establishing the diagnosis of NAFLD. Although fibrosis is common in pediatric NASH, cirrhosis has been described in only a few cases of childhood NAFLD. We describe a girl with childhood onset obesity presenting with hepatic cirrhosis.

The purpose of the present study was to assess the effect of an exercise training program conducted concurrently with a high-fat (HF)-diet regimen on the induction of hepatic steatosis. Two groups of rats were fed either a standard (SD) or a HF (40% kcal) diet for 8 wk and were additionally assigned either to a sedentary (Sed) or a treadmill-trained (TR) group. Training (5 days/wk) was initiated at the same time as the HF diet and was progressively increased, reaching 60 min at 26 m/min, 10% grade, for the last 4 wk. At the end of the 8-wk period, HF-Sed rats exhibited ∼72% higher liver triacylglycerol concentration than SD-Sed rats (means ± SE: 17.15 ± 1.5 vs. 9.98 ± 1.0 mg/g; P < 0.01). Histological quantification of lipid infiltration, with the use of an image analysis computing system, revealed that, although fat was mainly stored as microvesicles (2), the HF-diet-induced hepatic steatosis occurred via the accumulation of macrovesicles (>1 μm2). Concurrent exercise training completely prevented the HF-diet-induced hepatic steatosis. The surface area of liver parenchyma infiltrated by lipid vacuoles was similar in HF-TR as in SD-Sed rats (26.4 ± 1.8 vs. 29.3 ± 5.9 × 103μm2/200,000 μm2of liver parenchyma, respectively; P> 0.05). The different states of liver lipid infiltration after the HF diet in Sed and TR rats were associated with similar changes in plasma free fatty acids and glycerol, as well as with similar changes in fat pad weights, but not with plasma triacylglycerol levels. It is concluded that, after a HF-diet regimen of 8 wk in rats, hepatic steatosis occurs primarily via the accumulation of lipid as macrovesicles. Exercise training pursued at the same time completely prevents the HF-diet-induced macrovesicular hepatic steatosis.

Purpose: To investigate the feasibility of in vivo assessment of hepatic lipid composition using 3.0-T proton magnetic resonance spectroscopy ((1)H-MRS) in a steatotic rat model and compare it to histopathological and biochemical assessment. Materials and Methods: Hepatic steatosis was induced by feeding rats with a methionine/choline-deficient (MCD) diet for 1, 2, 3, 5 or 7 weeks (n=5 per group). At the end of the diet period, (1)H-MRS of the liver was performed, and rats were sacrificed for histopathological and biochemical assessment of the liver. Spectra were acquired in a single voxel (1.2 cc) using a point-resolved spectroscopic sequence with TE/TR=35/2000 ms and 64 signal acquisitions. From the MR spectra, peak area ratios were calculated to estimate hepatic lipid composition. Results: During MCD diet periods, hepatic steatosis significantly increased on histopathology (P

Altered hepatic lipid homeostasis, hepatocellular injury, and inflammation are features of nonalcoholic steatohepatitis, which contributes significantly to liver-related morbidity and mortality in the Western population. A collection of inflammatory mediators have been implicated in the pathogenesis of steatohepatitis in mouse models. However, the pathways essential for coordination and amplification of hepatic inflammation and injury caused by steatosis are not completely understood. We tested the hypothesis that tissue factor (TF)-dependent thrombin generation and the thrombin receptor protease activated receptor-1 (PAR-1) contribute to liver inflammation induced by steatosis in mice. Wild-type C57Bl/6J mice fed a diet deficient in methionine and choline for 2 weeks manifested steatohepatitis characterized by increased serum alanine aminotransferase activity, macrovesicular hepatic steatosis, hepatic inflammatory gene expression, and lobular inflammation. Steatohepatitis progression was associated with thrombin generation and hepatic fibrin deposition. Coagulation cascade activation was significantly reduced in low TF mice, which express 1% of normal TF levels. Hepatic triglyceride accumulation was not affected in low TF mice or PAR-1-deficient mice. In contrast, biomarkers of hepatocellular injury, inflammatory gene induction, and hepatic accumulation of macrophages and neutrophils were greatly reduced by TF-deficiency and PAR-1-deficiency. The results suggest that TF-dependent thrombin generation and activation of PAR-1 amplify hepatic inflammation and injury during the pathogenesis of steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) results from the excessive deposition of fat within liver cells (hepatocytes). It is the most common cause of liver disease in the pediatric population.1 The pathologic lesion that is the hallmark of NAFLD (macrovesicular hepatic steatosis) may be present in as many as 1 of every 10 children.1 The disease has a wide spectrum of possible pathologic outcomes.2 The reasons for the variability in outcome are unknown, but many factors are probably involved. Because of the increasing prevalence of NAFLD, it is critical to understand why some patients have a more benign course whereas in others it may progress to fibrosis, cirrhosis, and, eventually, end-stage liver disease.3 A fundamental molecular understanding of the pathophysiology of NAFLD is needed and is being actively pursued. Oxidative stress seems to be a very important trigger of inflammation in the liver.4 It … Address correspondence to Neal S. LeLeiko, MD, PhD, Hasbro Children's Hospital/Rhode Island Hospital, Division of Pediatric Gastroenterology, Nutrition, and Liver Diseases, 593 Eddy St, MPH 131, Providence, RI 02906. E-mail: neal_leleiko{at}brown.edu

Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of adults in the United States and is associated with obesity, metabolic syndrome, type II diabetes and hepatocellular carcinoma (HCC). Here we report spontaneous insulin resistance, NAFLD and HCC with parent-specific inheritance in AxB mice. Helicobacter-free F1 offspring (n=59) from wildtype C57BL/6 and A/JCr parents were maintained on a standard chow diet and evaluated at 3, 9 and 15 months. ABF1 (A/J dam x B6 sire) but not BAF1 males (B6 dam x A/J sire) developed progressively severe mixed microvesicular and macrovesicular hepatic steatosis resulting in sporadic HCC. Females were unaffected. NAFLD in males was a component of metabolic syndrome characterized by hyperinsulinemia, hypercholesterolemia and increased body mass (all P

To retrospectively compare the accuracy of visual grading and the liver attenuation index in the computed tomographic (CT) diagnosis of 30% or higher macrovesicular steatosis in living hepatic donors, by using histologic analysis as the reference standard.Institutional review board approval was obtained with waiver of informed consent. Of 703 consecutive hepatic donor candidates, 24 patients (22 men and two women; mean age +/- standard deviation, 36.3 years +/- 9.7) who had 30% or higher macrovesicular steatosis at histologic analysis and same-day CT with subsequent needle biopsy in the right hepatic lobe (at least two samples per patient) were evaluated. An age- and sex-matched control group of 24 subjects included those who had less than 30% macrovesicular steatosis but otherwise met the same criteria as the patient group. A diagnostically difficult setting was made by selecting those with the highest degree of macrovesicular steatosis when there were multiple control subjects matched for a particular subject in the patient group. Two independent radiologists assessed steatosis of the right hepatic lobe by using two methods: a five-point visual grading system that used attenuation comparison between the liver and hepatic vessels and the liver attenuation index (CT(L-S)), defined as hepatic attenuation minus splenic attenuation and calculated with region of interest measurements of hepatic attenuation. Interobserver agreement was assessed. Accuracy in the diagnosis of 30% or higher macrovesicular steatosis was compared by using a multireader, multicase receiver operating characteristic (ROC) analysis.For visual grading, kappa = 0.905 (95% confidence interval [CI]: 0.834, 0.976). Intraclass correlation coefficient for CT(L-S) was 0.962 (95% CI: 0.893, 0.983). The area under the ROC curve of visual grading and CT(L-S) were 0.927 (95% CI: 0.822, 1) and 0.929 (95% CI: 0.874, 0.983), respectively, indicating no statistically significant difference (P = .975).Both visual grading and CT(L-S) are highly reliable and similarly accurate in the diagnosis of 30% or higher macrovesicular steatosis in living hepatic donor candidates.

Macrovesicular hepatic steatosis has a lower tolerance to reperfusion injury than microvesicular steatosis with an abnormally high ratio of omega-6 (n-6): omega-3 (n-3) polyunsaturated fatty acids (PUFAs). We investigated the influence of PUFAs on microcirculation in steatotic livers and the potential to minimize reperfusion injury in the macrosteatotic liver by normalization of PUFAs. Ob/ob mice were used as a model of macrovesicular hepatic steatosis and C57/Bl6 mice fed a choline-deficient diet for microvesicular steatosis. Steatotic and lean livers were subjected to 45 minutes of ischemia and 3 hours of reperfusion. Hepatic content of omega-3 and omega-6 PUFAs was determined. Microcirculation was investigated using intravital fluorescence microscopy. A second group of ob/ob mice was supplemented with dietary omega-3 PUFAs and compared with the control diet–fed group. Microcirculation, AST, and Kupffer cell activity were assessed. Macrosteatotic livers had significant microcirculatory dysfunction correlating with high omega-6: omega-3 PUFA ratio. Dietary omega-3 PUFA resulted in normalization of this ratio, reduction of intrahepatic lipids, and decrease in the extent of macrosteatosis. Defective microcirculation was dramatically ameliorated with significant reduction in Kupffer cell activity and protection against hepatocellular injury both before ischemia and after reperfusion. Conclusion: Macrosteatotic livers disclosed an abnormal omega-6: omega-3 PUFA ratio that correlates with a microcirculatory defect that enhanced reperfusion injury. Thus, protective strategies applied during or after ischemia are unlikely to be useful. Preoperative dietary omega-3 PUFAs protect macrosteatotic livers against reperfusion injury and might represent a valuable method to expand the live liver donor pool. (HEPATOLOGY 2007;45:855–863.)

To determine prospectively the diagnostic performance of unenhanced computed tomography (CT) in the assessment of macrovesicular steatosis in potential donors for living donor liver transplantation by using same-day biopsy as a reference standard.Institutional review board approval and informed consent were obtained. A total of 154 candidates, including 104 men (mean age, 30.2 years +/- 10.3 [standard deviation]) and 50 women (mean age, 31.8 years +/- 11.2), underwent same-day unenhanced CT and ultrasonography-guided liver biopsy. Histologic degree of macrovesicular steatosis was determined. Three liver attenuation indices were derived: liver-to-spleen attenuation ratio (CT(L)(/S)), difference between hepatic and splenic attenuation (CT(L)(-S)), and blood-free hepatic parenchymal attenuation (CT(LP)). Regression equations were used to quantitatively estimate the degree of macrovesicular steatosis. Limits of agreement between estimated macrovesicular steatosis and the reference standard were calculated. Receiver operating characteristic analyses were used to determine the performance of each index for qualitative diagnosis of macrovesicular steatosis of 30% or greater. The cutoff value that provided a balance between sensitivity and specificity and the highest cutoff value that yielded 100% specificity were determined.Limits of agreement were -14% to 14% for CT(L)(/S) and CT(L)(-S) and -13% to 13% for CT(LP). Performance in diagnosing macrovesicular steatosis of 30% or greater was not significantly different among indices (P.05). Cutoff values of 0.9, -7, and 58 were determined for CT(L)(/S), CT(L)(-S), and CT(LP), respectively, and provided a balance between sensitivity and specificity. Cutoff values of 0.8, -9, and 42 were determined for CT(L)(/S), CT(L)(-S), and CT(LP), respectively, and yielded 100% specificity for all indices, with corresponding sensitivities of 82%, 82%, and 73% for CT(L)(/S), CT(L)(-S), and CT(LP), respectively.Diagnostic performance of unenhanced CT for quantitative assessment of macrovesicular steatosis is not clinically acceptable. Unenhanced CT, however, provides high performance in qualitative diagnosis of macrovesicular steatosis of 30% or greater.

To assess degree of macrovesicular steatosis with unenhanced computed tomography (CT) and correlate it with histologic findings in potential donors for living related liver transplantation.Forty-two candidates underwent unenhanced CT within 4 weeks of core liver biopsy. An experienced liver pathologist, blinded to both CT and surgical findings, retrospectively reviewed biopsy specimens and determined degree of macrovesicular steatosis. A radiologist blinded to histologic grading calculated mean hepatic attenuation in each donor liver by averaging 25 region-of-interest (ROI) measurements on five sections (five ROIs per section). Mean splenic attenuation was calculated with three separate ROI measurements. Liver attenuation index (LAI) was derived and defined as the difference between mean hepatic and mean splenic attenuation. Body mass index (BMI) was determined for each patient. Linear regression analysis was used to correlate degree of macrovesicular steatosis with both LAI and BMI.LAI correctly predicted degree of macrovesicular steatosis in 38 (90%) of 42 cases. In four of four livers, LAI below -10 HU correlated with greater than 30% macrovesicular steatosis (unacceptable for liver transplantation). In nine of 11 livers, LAI was between -10 and 5 HU and correctly predicted 6%-30% steatosis (relative contraindication). In two of 11 cases, LAI overestimated degree of hepatic steatosis. LAI above 5 HU correctly predicted 0%-5% steatosis in 25 of 27 livers. In two of 27 cases, parenchymal hemosiderin deposition led to an increase in LAI into the normal range, despite mild histologically confirmed steatosis. Degree of histologic macrovesicular steatosis correlated well with LAI (r = 0.92) and marginally with BMI (r = 0.45). Of 27 potential donors with normal livers at CT and acceptable LAI levels, four (15%) were deemed poor donor candidates because core biopsy revealed subtle hepatic necrosis and nonspecific hepatitis.Although unenhanced CT quantifies the degree of macrovesicular steatosis relatively well, it may preclude a liver biopsy only in a small percentage of potential donors with low LAI (unacceptable degree of steatosis). Core liver biopsy is still necessary in the majority of donors with normal LAI to identify those with both fatty liver and coexistent hemosiderin deposition or radiologically occult diffuse liver diseases.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions characterized histologically by mainly macrovesicular hepatic steatosis and occurs in those who do not consume alcohol in amounts generally considered to be harmful to the liver. There are 2 histologic patterns of NAFLD: fatty liver alone and steatohepatitis. NAFLD is an increasingly recognized cause of liver-related morbidity and mortality. In this review, the existing literature regarding the nomenclature, clinical and histologic spectrum, natural history, diagnosis, and management of this condition are discussed. GASTROENTEROLOGY 2002;123:1705-1725

Chanarin-Dorfman syndrome (CDS) is a multisystem, autosomal recessive genetic disorder characterized by congenital non-bullous ichthyosiform erythroderma with accumulation of lipid droplets in granulocytes and basal keratinocytes. An 18-month-old female child presented with typical dermatological features of CDS. She was born as a collodion baby. Liver biopsy showed micronodular cirrhosis along with macrovesicular hepatic steatosis. Sequencing of all exons and exon-intron boundaries of the ABHD5 gene showed that the patient was homozygous for a novel mutation g.24947delG (c.773 + 1delG) in intron 5. This is the first Indian child with mutation proven CDS.

Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of adults in the United States and is associated with obesity, metabolic syndrome, type II diabetes and hepatocellular carcinoma (HCC). Here we report spontaneous insulin resistance, NAFLD and HCC with parent-specific inheritance in AxB mice. Helicobacter-free F1 offspring (n=59) from wildtype C57BL/6 and A/JCr parents were maintained on a standard chow diet and evaluated at 3, 9 and 15 months. ABF1 (A/J dam x B6 sire) but not BAF1 males (B6 dam x A/J sire) developed progressively severe mixed microvesicular and macrovesicular hepatic steatosis resulting in sporadic HCC. Females were unaffected. NAFLD in males was a component of metabolic syndrome characterized by hyperinsulinemia, hypercholesterolemia and increased body mass (all P