Nonsteatotic Livers Research Articles

The role of Neuregulin-1 in steatotic and non-steatotic liver transplantation from donors after cardiocirculatory death

Liver grafts from donors after cardiocirculatory death (DCDs) are sometimes not considered for liver transplantation (LT). Plasma Neuregulin-1 (NRG1) is altered in cardiac abnormalities and the liver is one of the most important targets of NRG1. We study the role of NRG1 in DCD LT. Under these conditions, NRG1 was pharmacologically modulated and their pathways were characterized. NRG1 levels were increased in steatotic and non-steatotic grafts from DCDs; NRG1 was derived from adipose tissue. When NRG1 was inhibited, injury and inflammation were exacerbated. The benefits of endogenous NRG1 in DCD grafts were associated with increased hepatic accumulation of adipocyte-derived vascular endothelial growth factor-A (VEGFA). The Id1-Wnt2 signaling pathway was involved in the action mechanisms of endogenous VEGFA. Exogenous NRG1 exacerbated damage and inflammation. Here differential role of NRG1 (endogenous versus exogenous) was demonstrated and VEGFA treatment was proposed as a highly protective strategy in steatotic and non-steatotic DCD LT.

Evaluation of MRI proton density fat fraction in hepatic steatosis: a systematic review and meta-analysis.

Amidst the global rise of metabolic dysfunction-associated steatotic liver disease (MASLD), driven by increasing obesity rates, there is a pressing need for precise, non-invasive diagnostic tools. Our research aims to validate MRI Proton Density Fat Fraction (MRI-PDFF) utility, compared to liver biopsy, in grading hepatic steatosis in MASLD. A systematic search was conducted across Embase, PubMed/Medline, Scopus, and Web of Science until January 13, 2024, selecting studies that compare MRI-PDFF with liver biopsy for hepatic steatosis grading, defined as grades 0 (< 5% steatosis), 1 (5-33% steatosis), 2 (34-66% steatosis), and 3 (> 66% steatosis). Twenty-two studies with 2844 patients were included. The analysis showed high accuracy of MRI-PDFF with AUCs of 0.97 (95% CI = 0.96-0.98) for grade 0 vs ≥ 1, 0.91 (95% CI = 0.88-0.93) for ≤ 1 vs ≥ 2, and 0.91 (95% CI = 0.88-0.93) for ≤ 2 vs 3, diagnostic odds ratio (DOR) from 98.74 (95% CI = 58.61-166.33) to 23.36 (95% CI = 13.76-39.68), sensitivity and specificity from 0.93 (95% CI = 0.88-0.96) to 0.76 (95% CI = 0.63-0.85) and 0.93 (95% CI = 0.88-0.96) to 0.89 (95% CI = 0.84-0.93), respectively. Likelihood ratio (LR) + ranged from 13.3 (95% CI = 7.4-24.0) to 7.2 (95% CI = 4.9-10.5), and LR - from 0.08 (95% CI = 0.05-0.13) to 0.27 (95% CI = 0.17-0.42). The proposed MRI-PDFF threshold of 5.7% for liver fat content emerges as a potential cut-off for the discrimination between grade 0 vs ≥ 1 (p = 0.075). MRI-PDFF is a precise non-invasive technique for diagnosing and grading hepatic steatosis, warranting further studies to establish its diagnostic thresholds. This study underscores the high diagnostic accuracy of MRI-PDFF for distinguishing between various grades of hepatic steatosis for early detection and management of MASLD, though further research is necessary for broader application. MRI-PDFF offers precision in diagnosing and monitoring hepatic steatosis. The diagnostic accuracy of MRI-PDFF decreases as the grade of hepatic steatosis advances. A 5.7% MRI-PDFF threshold differentiates steatotic from non-steatotic livers.

Magnetic resonance imaging T1 mapping of the liver, pancreas and spleen in children

PurposeTo characterize T1 relaxation times of the pancreas, liver, and spleen in children with and without abdominal pathology.MethodsThis retrospective study included pediatric patients (< 18-years-old). T1 mapping was performed with a Modified Look-Locker Inversion Recovery sequence. Patients were grouped based on review of imaging reports and electronic medical records. The Kruskal–Wallis test with Dunn’s multiple comparison was used to compare groups.Results220 participants were included (mean age: 11.4 ± 4.2 years (1.5 T); 10.9 ± 4.5 years (3 T)). Pancreas T1 (msec) was significantly different between subgroups at 1.5 T (p < 0.0001). Significant pairwise differences included: normal (median: 583; IQR: 561–654) vs. acute pancreatitis (731; 632–945; p = 0.0024), normal vs. chronic pancreatitis (700; 643–863; p = 0.0013), and normal vs. acute + chronic pancreatitis (1020; 897–1099; p < 0.0001). Pancreas T1 was also significantly different between subgroups at 3 T (p < 0.0001). Significant pairwise differences included: normal (779; 753–851) vs. acute pancreatitis (1087; 910–1259; p = 0.0012), and normal vs. acute + chronic pancreatitis (1226; 1025–1367; p < 0.0001).Liver T1 was significantly different between subgroups only at 3 T (p = 0.0011) with pairwise differences between normal (818, 788–819) vs. steatotic (959; 848–997; p = 0.0017) and normal vs. other liver disease (882; 831–904; p = 0.0455). Liver T1 was weakly correlated with liver fat fraction at 1.5 T (r = 0.39; 0.24–0.52; p < 0.0001) and moderately correlated at 3 T (r = 0.64; 0.49–0.76; p < 0.0001).There were no significant differences in splenic T1 relaxation times between subgroups.ConclusionPancreas T1 relaxation times are higher at 1.5 T and 3 T in children with pancreatitis and liver T1 relaxation times are higher in children with steatotic and non-steatotic chronic liver disease at 3 T.

Dynamic changes in the mouse hepatic lipidome following warm ischemia reperfusion injury

Liver failure secondary to metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common cause for liver transplantation in many parts of the world. Moreover, the prevalence of MASLD not only increases the demand for liver transplantation, but also limits the supply of suitable donor organs because steatosis predisposes grafts to ischemia–reperfusion injury (IRI). There are currently no pharmacological interventions to limit hepatic IRI because the mechanisms by which steatosis leads to increased injury are unclear. To identify potential novel mediators of IRI, we used liquid chromatography and mass spectrometry to assess temporal changes in the hepatic lipidome in steatotic and non-steatotic livers after warm IRI in mice. Our untargeted analyses revealed distinct differences between the steatotic and non-steatotic response to IRI and highlighted dynamic changes in lipid composition with marked changes in glycerophospholipids. These findings enhance our knowledge of the lipidomic changes that occur following IRI and provide a foundation for future mechanistic studies. A better understanding of the mechanisms underlying such changes will lead to novel therapeutic strategies to combat IRI.

Deep Learning–Based Survival Analysis for Receiving a Steatotic Donor Liver Versus Waiting for a Standard Liver

An emerging strategy to expand the donor pool is the use of a steatotic donor liver (SDLs; ≥ 30% macrosteatosis on biopsy). With the obesity epidemic and prevalence of nonalcoholic fatty liver disease, SDLs have been reported in 59% of all deceased donors. Many potential candidates need to decide whether to accept an SDL offer or remain on the waitlist for a nonsteatotic donor liver (non-SDL). The objective of this study was to compare the survival of accepting an SDL vs using a non-SDL after waiting various times. Using data from the United States' organ procurement and transplantation network, deep survival learning predictive models were built to compare post-decision survival after accepting an SDL vs waiting for a non-SDL. The comparison subjects contain simulated 20,000 different scenarios of a candidate either accepting an SDL immediately or receiving a non-SDL after waiting various times. The research variables were selected using the LASSO-Cox and Random Survival Forest (RSF) models. The Cox proportional hazards and RSF models were also comparatively included for survival prediction. In addition, personalized survival curves for randomly selected candidates were generated. Deep survival learning outperformed Cox proportional hazards and RSF in predicting the survival of liver transplants. Among the simulations, 25% to 30% of scenarios demonstrated a higher 3-year survival post-decision for candidates accepting an SDL than waiting and receiving a non-SDL. The difference was only 1.43% in 3-year survival post-decision between accepting an SDL and waiting 260 days (mean waitlist time) for a non-SDL. As the number of days on the waitlist increases, the difference in survival between accepting SDLs and waiting for non-SDLs decreases. Appropriately used SDLs could expand the donor pool and relieve the candidates' unmet need for donor livers, which presents long-term survival benefits for recipients.

Overcoming the hurdles of steatotic grafts in liver transplantation: Insights into survival and prognostic factors.

With increasing metabolic dysfunction-associated steatotic liver disease, the use of steatotic grafts in liver transplantation (LT) and their impact on postoperative graft survival (GS) needs further exploration. Analyzing adult LT recipient data (2002-2022) from the United Network for Organ Sharing database, outcomes of LT using steatotic (≥30% macrosteatosis) and nonsteatotic donor livers, donors after circulatory death, and standard-risk older donors (age 45-50) were compared. GS predictors were evaluated using Kaplan-Meier and Cox regression analyses. Of the 35,345 LT donors, 8.9% (3,155) were fatty livers. The initial 30-day postoperative period revealed significant challenges with fatty livers, demonstrating inferior GS. However, the GS discrepancy between fatty and nonfatty livers subsided over time ( p = 0.10 at 5y). Long-term GS outcomes showed comparable or even superior results in fatty livers relative to nonsteatotic livers, conditional on surviving the initial 90 postoperative days ( p = 0.90 at 1y) or 1 year ( p = 0.03 at 5y). In the multivariable Cox regression analysis, the high body surface area (BSA) ratio (≥1.1) (HR 1.42, p = 0.02), calculated as donor BSA divided by recipient BSA, long cold ischemic time (≥6.5h) (HR 1.72, p < 0.01), and recipient medical condition (intensive care unit hospitalization) (HR 2.53, p < 0.01) emerged as significant adverse prognostic factors. Young (<40y) fatty donors showed a high BSA ratio, diabetes, and intensive care unit hospitalization as significant indicators of a worse prognosis ( p < 0.01). Our study emphasizes the initial postoperative 30-day survival challenge in LT using fatty livers. However, with careful donor-recipient matching, for example, avoiding the use of steatotic donors with long cold ischemic time and high BSA ratios for recipients in the intensive care unit, it is possible to enhance immediate GS, and in a longer time, outcomes comparable to those using nonfatty livers, donors after circulatory death livers, or standard-risk older donors can be anticipated. These novel insights into decision-making criteria for steatotic liver use provide invaluable guidance for clinicians.

NO-IL-6/10-IL-1β axis: a new pathway in steatotic and non-steatotic liver grafts from brain-dead donor rats.

Brain death (BD) and steatosis are both risk factors for organ dysfunction or failure in liver transplantation (LT). Here, we examine the role of interleukin 6 (IL- 6) and IL-10 in LT of both non-steatotic and steatotic liver recovered from donors after brain death (DBDs), as well as the molecular signaling pathways underlying the effects of such cytokines. BD reduced IL-6 levels only in nonsteatotic grafts, and diminished IL-10 levels only in steatotic ones. In both graft types, BD increased IL-1β, which was associated with hepatic inflammation and damage. IL-6 administration reduced IL-1β only in non-steatotic grafts and protected them against damage and inflammation. Concordantly, IL-1β inhibition via treatment with an IL-1 receptor antagonist caused the same benefits in non-steatotic grafts. Treatment with IL-10 decreased IL-1β only in steatotic grafts and reduced injury and inflammation specifically in this graft type. Blockading the IL-1β effects also reduced damage and inflammation in steatotic grafts. Also, blockade of IL-1β action diminished hepatic cAMP in both types of livers, and this was associated with a reduction in liver injury and inflammation, then pointing to IL-1β regulating cAMP generation under LT and BD conditions. Additionally, the involvement of nitric oxide (NO) in the effects of interleukins was evaluated. Pharmacological inhibition of NO in LT from DBDs prompted even more evident reductions of IL-6 or IL-10 in non-steatotic and steatotic grafts, respectively. This exacerbated the already high levels of IL-1β seen in LT from DBDs, causing worse damage and inflammation in both graft types. The administration of NO donors to non-steatotic grafts potentiated the beneficial effects of endogenous NO, since it increased IL-6 levels, and reduced IL-1β, inflammation, and damage. However, treatment with NO donors in steatotic grafts did not modify IL-10 or IL-1β levels, but induced more injurious effects tan the induction of BD alone, characterized by increased nitrotyrosine, lipid peroxidation, inflammation, and hepatic damage. Our study thus highlights the specificity of new signaling pathways in LT from DBDs: NO-IL-6-IL-1β in non-steatotic livers and NO-IL-10-IL-1β in steatotic ones. This opens up new therapeutic targets that could be useful in clinical LT.

Diagnostic Performance of Quantitative Ultrasound Parameters in Non-alcoholic Fatty Liver Disease

Marked liver steatosis, steatohepatitis, and significant fibrosis are risk factors for unfavorable outcomes in non-alcoholic fatty liver disease (NAFLD). In this study, the diagnostic performance ofattenuation coefficient(AC), liver stiffness(LS), and dispersion slope (DS) was evaluated separately and combined in the diagnosis of liver steatosis and fibrosis in NAFLD suspects using biopsy or magnetic resonance imaging (MRI) as a reference standard. Seventy-four NAFLD suspects were prospectively imaged with an Aplio i800 ultrasound scanner (Canon Medical Systems, Tustin, CA). AC, LS, and DS measurements were obtained from the right liver lobe. Thirty-four patients underwent liver biopsy, and 40 had MRI. There were 32 patients (43%) with liver steatosis and fibrosis (S+F), 22(30%) with steatosis (S), 5 (7%) with fibrosis (F), and 15 (20%) with normal liver (N). Mean ACs were significantly higher in steatotic livers (n=54) than in non-steatotic livers (n=20) (P<0.0001). LS and DS were significantly higher in patients with liver fibrosis (n=37) compared tonon-fibrotic livers (n=37) (P=0.0004 and P=0.0002, respectively). In detecting (S+F), the area under the receiver operating characteristic curve (AUROCC) was 0.87 for combined ultrasound parameters of LS and AC (negative predictive value [NPV]: 75%, positive predictive value [PPV]: 77%, P<0.0001). In detecting patients with liver steatosis and fibrosis stage ≥2, LS had an AUROCC of 0.93 (NPV: 87%, PPV: 82%, P<0.0001). In the biopsy group, 32% (11/34) were diagnosed with non-alcoholic steatohepatitis (NASH). DS values showed a significant difference among patients with (n=23) or without (n=11) hepatocellular ballooning (P=0.02). AUROCC was 0.87 for combined ultrasound parameters of AC, LS, and DS with body mass index (BMI) in detecting NASH (NPV: 80%, PPV: 87%, P=0.0006). AC and LS showed high diagnostic value in detecting liver steatosis and fibrosis, respectively. The combined AC and LS values further improved the diagnostic accuracy in detecting NAFLD and high-risk NAFLD patients.

Small extracellular vesicles from HO-1-modified bone marrow-derived mesenchymal stem cells attenuate ischemia-reperfusion injury after steatotic liver transplantation by suppressing ferroptosis via miR-214-3p

Donor shortage is a major problem that limits liver transplantation availability. Steatotic donor liver presents a feasible strategy to solve this problem. However, severe ischemia-reperfusion injury (IRI) is an obstacle to the adoption of steatotic transplanted livers. Evidence from our prior studies indicated that bone marrow mesenchymal stem cells modified with heme oxygenase-1 (HMSCs) can attenuate non-steatotic liver IRI. However, the contribution of HMSCs in transplanted steatotic liver IRI is unclear. Here, HMSCs and their derived small extracellular vesicles (HM-sEVs) alleviated IRI in transplanted steatotic livers. After liver transplantation, there was significant enrichment of the differentially expressed genes in the glutathione metabolism and ferroptosis pathways, accompanied by ferroptosis marker upregulation. The HMSCs and HM-sEVs suppressed ferroptosis and attenuated IRI in the transplanted steatotic livers. MicroRNA (miRNA) microarray and validation experiments indicated that miR-214-3p, which was abundant in the HM-sEVs, suppressed ferroptosis by targeting cyclooxygenase 2 (COX2). In contrast, COX2 overexpression reversed this effect. Knockdown of miR-214-3p in the HM-sEVs diminished its ability to suppress ferroptosis and protect liver tissues/cells. The findings suggested that HM-sEVs suppressed ferroptosis to attenuate transplanted steatotic liver IRI via the miR-214-3p–COX2 axis.

Frequency of Hepatic Metastatic Disease in Patients with Stage IV Breast Cancer Is Similar for Steatotic and Non-Steatotic Livers.

Breast cancer is the most common non-cutaneous malignancy and the second leading cause of cancer mortality in the United States. Breast cancer is a heterogeneous disease; diagnosis at an early stage renders it potentially curable, whereas advanced metastatic disease carries a worse prognosis. To investigate whether hepatic steatosis (HS) is associated with liver metastases in patients with newly diagnosed stage IV female breast cancer patients (either de novo metastatic breast cancer or recurrent metastatic breast cancer) using non-contrast computed tomography (CT) as a marker of HS. Retrospective analysis. We retrospectively identified 168 patients with stage IV breast cancer with suitable imaging from a prospectively maintained oncologic database. Three radiologists manually defined hepatic regions of interest on non-contrast CT images, and attenuation data were extracted. HS was defined as a mean attenuation <48 Hounsfield units. The frequency of hepatic metastatic disease was calculated for patient with and without HS. Relationships between HS and various patient (age, body mass index, race) and tumor (hormone receptor status, HER2 status, tumor grade) characteristics were also analyzed. There were 4 patients with liver metastasis in the HS group (41 patients) versus 20 patients with liver metastases in the non-HS group (127 patients). The difference in frequencies of liver metastases among patients with (9.8%) versus without (15.7%) hepatic steatosis (odds ratio = 1.72 [0.53-7.39]) was not statistically significant (P = .45). Body mass index was significantly higher (P = .01) among patients with hepatic steatosis (32.2 ± 7.3 vs 28.8 ± 7.1 kg/m2). Otherwise, there were no significant differences between patients with versus without HS with respect to regarding age, race, hormone receptor status, HER2 status, or tumor grade. The frequency of hepatic metastatic disease in patients with stage IV breast cancer is similar for steatotic and non-steatotic livers.

Massive Single Lesion in a Patient With Sickle Cell Disease

Massive Single Lesion in a Patient With Sickle Cell Disease

The effect of steatotic donor livers on the prognosis of donors and recipients after pediatric living donor liver transplantation

Objectives: To evaluate the effects of steatotic donor livers on the safety of donors and the prognosis of donors and recipients in pediatric living donor liver transplantation. Methods: A total of 814 pediatric living donor liver transplantations were performed between January 2013 and December 2020 at Department of Pediatric Organ Transplantation,Tianjin First Central Hospital.The clinical data were collected and a retrospective study was conducted.The recipients and the donors were divided into non-steatotic donor liver group(n=733) and steatotic donor liver group(n=81) according to whether the donor graft had steatosis. The recipients and the donors in the steatotic donor liver group were further divided into mild and moderate steatosis groups based on the degree of liver steatosis.Among the donors of non-steatosis donor group,there were 307 males and 426 females,with a median age of 30 years(range:18 to 57 years);the recipients included 351 males and 382 females,with a median age of 7 months(range:4 month to 14 years).Among the donors of steatosis donor group,there were 41 males and 40 females,with a median age of 31 years(range:22 to 51 years);the recipients included 34 males and 47 females,with a median age of 8 months(range:5 months to 11 years).The donors and the recipients were followed up regularly by means of outpatient reexamination and questionnaire survey after operation.Statistical analysis of data between groups was performed using t-test,Wilcoxon rank-sum test,repeated measures ANOVA,χ2 test,or Fisher's exact test,respectively.The survival curves of recipients and grafts in different groups were created by Kaplan-Meier method,and the survival rates of the steatotic donor liver group and the non-steatotic donor liver group were compared by Log-rank method. Results: There was no significant difference in the gender of donors in both groups (P=0.132).There were significant differences in the age and blood type distribution as well as body weight and body mass index(all P<0.05) between the two groups.No significant difference was seen in the recovery of liver function markers ALT and AST at 1,2,5 days and 1 month after operation (all P>0.05) between the two groups.The steatotic donor liver group showed longer operation time ((294±75) minutes vs. (264±81) minutes; t=3.149,P=0.002),increased incidence of postoperative biliary leakage (3.7%(3/81) vs. 0.5% (4/733); P=0.025) and delayed incision healing (7.4%(6/81) vs. 2.0%(15/733); P=0.013).There were no significant differences in gender,age,blood type distribution,height,weight and pediatric end-stage liver disease score of recipients between the two groups (all P>0.05).As compared to the non-steatotic donor liver group,the steatotic donor liver group showed similar levels of ALT, AST and total bilirubin within 2 weeks after operation(all P>0.05). The cumulative recipient survival rates in both groups were both 96.3%,the cumulative graft survival rates were 96.3% and 95.5%,respectively,without significant difference(both P>0.05). No statistical difference was observed in the incidence of major complications between the two groups (all P>0.05). There was no significant difference in the recovery of liver function markers of donors and recipients between mild and moderate steatosis groups(all P>0.05).The cumulative recipient survival rates were both 95.9% and the cumulative graft survival rates were both 100% in mild and moderate steatosis groups,without significant difference(P=0.592). Conclusions: The application of mild to moderate steatotic donor livers in pediatric living donor liver transplantation may prolong the operation time of donors,increase the incidence of complications such as biliary leakage and delayed incision healing. But there is no significant impact of mild to moderate steatotic donor livers on the overall postoperative recovery of donors and recipients,and the prognosis is ideal.

MRI with diffusion-weighted image in assessment of hepatic fibrosis and steatosis

Background FibroScan and diffusion MRI have been recommended for staging and noninvasive diagnosis of hepatic fibrosis and steatosis. Aim To evaluate the diagnostic efficiency of conventional MRI and diffusion-weighted imaging in diagnosis and staging of hepatic fibrosis and steatosis. Patients and methods This research was conducted on 30 patients proven to have hepatic fibrosis or steatosis based on clinical, laboratory, and/or ultrasonographic criteria. Both sexes were included. Their age ranged from 20 to 60 years. The participants were sent to the MRI Unit in the Department of Radiodiagnosis, Tanta University Hospitals, over a period of 12 months from March 2021 till March 2022. Results There was a significant difference between apparent diffusion coefficient values of F0 and F1, F3, and F4 (P=0.010, 0.041, and 0.019, respectively); however, no significant difference was observed among the other various fibrosis stages. Conclusions FibroScan is a good noninvasive route for detection of hepatic fibrosis and steatosis. It can differentiate among various phases of hepatic fibrosis and steatosis. MRI can differentiate between fibrotic and nonfibrotic liver and also steatotic from nonsteatotic liver. However, it cannot differentiate between various phases of hepatic fibrosis and steatosis, especially the intermediate stages.

Type 1 Innate Lymphoid Cells Are Proinflammatory Effector Cells in Ischemia-Reperfusion Injury of Steatotic Livers.

Innate lymphoid cells (ILCs), the most recently described family of lymphoid cells, play fundamental roles in tissue homeostasis through the production of key cytokine. Group 1 ILCs, comprised of conventional natural killer cells (cNKs) and type 1 ILCs (ILC1s), have been implicated in regulating immune-mediated inflammatory diseases. However, the role of ILC1s in nonalcoholic fatty liver disease (NAFLD) and ischemia-reperfusion injury (IRI) is unclear. Here, we investigated the role of ILC1 and cNK cells in a high-fat diet (HFD) murine model of partial warm IRI. We demonstrated that hepatic steatosis results in more severe IRI compared to non-steatotic livers. We further elicited that HFD-IRI mice show a significant increase in the ILC1 population, whereas the cNK population was unchanged. Since ILC1 and cNK are major sources of IFN-γ and TNF-α, we measured the level of ex vivo cytokine expression in normal diet (ND)-IRI and HFD-IRI conditions. We found that ILC1s in HFD-IRI mice produce significantly more IFN-γ and TNF-α when compared to ND-IRI. To further assess whether ILC1s are key proinflammatory effector cells in hepatic IRI of fatty livers, we studied both Rag1 −/− mice, which possess cNK cells, and a substantial population of ILC1s versus the newly generated Rag1 −/− Tbx21 −/− double knockout (Rag1-Tbet DKO) mice, which lack type 1 ILCs, under HFD IRI conditions. Importantly, HFD Rag1-Tbet DKO mice showed significant protection from hepatic injury upon IRI when compared to Rag1 −/− mice, suggesting that T-bet-expressing ILC1s play a role, at least in part, as proinflammatory effector cells in hepatic IRI under steatotic conditions.

The Role of Neuregulin-1 in Steatotic and Non-Steatotic Liver Transplantation from Brain-Dead Donors.

Background. Brain death (BD) and steatosis are key risk factors to predict adverse post-transplant outcomes. We investigated the role of Neuregulin-1 (NRG1) in rat steatotic and non-steatotic liver transplantation (LT) from brain death donors (DBD). Methods: NRG1 pathways were characterized after surgery. Results: NRG1 and p21-activated kinase 1 (PAK1) levels increased in steatotic and non-steatotic grafts from DBDs. The abolishment of NRG1 effects reduced PAK1. When the effect of either NRG1 nor PAK1 was inhibited, injury and regenerative failure were exacerbated. The benefits of the NRG-1-PAK1 axis in liver grafts from DBDs were associated with increased vascular endothelial growth factor-A (VEGFA) and insulin growth factor-1 (IGF1) levels, respectively. Indeed, VEGFA administration in non-steatotic livers and IGF1 treatment in steatotic grafts prevented damage and regenerative failure resulting from the inhibition of either NRG1 or PAK-1 activity in each type of liver. Exogenous NRG1 induced greater injury than BD induction. Conclusions: This study indicates the benefits of endogenous NRG1 in liver grafts from DBDs and underscores the specificity of the NRG1 signaling pathway depending on the type of liver: NRG1-PAK1-VEGFA in non-steatotic livers and NRG1-PAK1-IGF1 in steatotic livers. Exogenous NRG1 is not an appropriate strategy to apply to liver grafts from DBD.

Nonalcoholic non-virus-related hepatocellular carcinoma arising from nonsteatotic liver: Clinical and pathological features.

Nonalcoholic non-virus-related hepatocellular carcinoma (NANV-HCC) is considered to occur in steatotic livers; however, emerging evidence indicates that a subset of NANV-HCC occurs in nonsteatotic livers. Currently, little information is available regarding this subset. This study sought to provide the clinical and pathological features of NANV-HCC in nonsteatotic livers.We retrospectively investigated the clinicopathological features of 101 consecutive patients with NANV-HCC treated with a curative-intent hepatectomy. A background liver with <5% steatosis by area was regarded as a nonsteatotic liver. Survivals of patient subgroups were estimated using the Kaplan–Meier method, and log-rank tests were conducted to assess the survival difference. Multivariate analysis was performed with the Cox proportional hazards method.Overall, 34 of 101 patients with NANV-HCC were found to have a nonsteatotic liver. Vascular invasion of the tumor was more frequently observed in patients with a nonsteatotic liver than in those with a steatotic liver (P = .03). The extent of lobular inflammation and fibrosis did not differ between patients with and without steatosis in the liver. NANV-HCC with a nonsteatotic liver was independently associated with a shorter disease-free survival (DFS) (hazard ratio [HR] 2.14; 95% confidence interval [CI] 1.21–3.80; P = .009) and a shorter overall survival (OS) (HR 2.79; 95% CI 1.27–6.16; P = .01) than NANV-HCC with a steatotic liver.The absence of steatosis in the liver is independently associated with shorter DFS and OS in patients with NANV-HCC. Our findings indicate that nonsteatotic liver can be a surrogate phenotype of aggressive NANV-HCC.

Unenhanced computed tomography for non-invasive diagnosis of hepatic steatosis with low tube potential protocol.

Lowering kVp affects the image contrast and computed tomography (CT) attenuation values of low kVp CT is different from those of conventional 120-kVp scans. The purpose of this study is to determine the diagnostic performance and to establish the reference range of low-kVp unenhanced CT for the assessment of hepatic steatosis in liver transplantation donors using magnetic resonance (MR) spectroscopy as a reference standard. This retrospective study included 165 potential donors (male:female =114:51, 36.5±12.0 years old) who underwent 100-kVp single-slice unenhanced CT scan and MR spectroscopy. The difference between hepatic and splenic attenuation (CTL-S) and liver-to-spleen attenuation ratio (CTL/S) were calculated. Reference standard was the fat signal fraction measured by MR spectroscopy. Limits of agreement between CT measurements and the reference standard were calculated. Areas under receiver operating characteristic curves (AUROCs) of CTL-S and CTL/S were compared for the diagnosis of moderate to severe steatosis. Cut-off values of CTL-S and CTL/S that provided a balance between sensitivity and specificity and the highest specificity using the lower limit of the reference range were calculated. Eighty-seven subjects had a non-steatotic liver. Sixty-one subjects had mild steatosis and 17 subjects had moderate to severe steatosis based on MR spectroscopy. CTL-S and CTL/S values were negatively correlated with the fat signal fraction (P<0.001) and limits of agreement were -8.4% to 8.4% for CTL-S and -9.6% to 9.6% for CTL/S. AUROCs of CTL-S and CTL/S for diagnosing moderate to severe steatosis were 0.956 and 0.957, respectively. Cut-off values of CTL-S and CTL/S for diagnosis of moderate to severe steatosis by the Youden index were -0.5 HU for CTL-S and 0.99 for CTL/S. Reference ranges of non-steatotic liver were -6.90 to 31.40 HU for CTL-S and 0.89 to 1.77 for CTL/S. Using -6.9 HU for CTL-S and 0.89 for CTL/S as cut-off values, the sensitivity and specificity for diagnosing moderate to severe steatosis were 70.59% and 90.54% (CTL-S) and 76.47% and 90.54% (CTL/S), respectively. Measurements from a low-kVp unenhanced CT scan were negatively correlated with the degree of hepatic steatosis. Low-kVp unenhanced CT is a robust technique with reduced radiation exposure for diagnosing moderate to severe hepatic steatosis.

Hepatic Steatosis Detection Using Differential Effective Permittivity

Hepatic steatosis is a disorder with high prevalence among obese people. Traditional imaging modalities are more common in hepatic steatosis diagnosis, but they are not suitable for monitoring or treatment evaluation. This study aims at developing a new technique suitable for electromagnetic (EM) tool in the microwave band to differentiate steatotic from nonsteatotic liver. A differential permittivity estimation method for hepatic steatosis detection is proposed. First, the effective permittivity of the right side of the torso is estimated based on the phase difference of EM waves traveling along symmetric paths within the torso. Then, permittivity modeling and statistical frequency selection are performed to model the estimated values and to extract reliable frequency samples. Finally, the percentage of the difference between the permittivity of the left and right sides of the torso is calculated over the selected samples. The effectiveness of the proposed method is validated using simulated signals and phantom measurements. The analyzed results reveal higher contrast between the average permittivity of the left and right sides of the torso for cases with hepatic steatosis (average contrast of 29.2%) compared to those with healthy liver (average contrast of 7.9%). The proposed method can differentiate between steatotic and nonsteatotic liver. It is suitable for clinical applications due to its robustness to unwanted noise and interferences, as well as errors in placement of sensors. The results verify the potential of EM devices, which could overcome shortcomings of traditional imaging techniques by being safe, cost-effective, and portable.

Liver Enhancement on Computed Tomography Is Suboptimal in Patients with Liver Steatosis.

This study’s aim was twofold. Firstly, to assess liver enhancement quantitatively and qualitatively in steatotic livers compared to non-steatotic livers on portal venous computed tomography (CT). Secondly, to determine the injection volume of contrast medium in patients with severe hepatic steatosis to improve the image quality of the portal venous phase. We retrospectively included patients with non-steatotic (n = 70), the control group, and steatotic livers (n = 35) who underwent multiphase computed tomography between March 2016 and September 2020. Liver enhancement was determined by the difference in attenuation in Hounsfield units (HU) between the pre-contrast and the portal venous phase, using region of interests during in three different segments. Liver steatosis was determined by a mean attenuation of ≤40 HU on unenhanced CT. Adequate enhancement was objectively defined as ≥50 ΔHU and subjectively using a three-point Likert scale. Enhancement of non-steatotic and steatotic livers were compared and associations between enhancement and patient- and scan characteristics were analysed. Enhancement was significantly higher among the control group (mean 51.9 ± standard deviation 11.5 HU) compared to the steatosis group (40.6 ± 8.4 HU p for difference < 0.001). Qualitative analysis indicated less adequate enhancement in the steatosis group: 65.7% of the control group was rated as good vs. 8.6% of the steatosis group. We observed a significant correlation between enhancement, and presence/absence of steatosis and grams of iodine per total body weight (TBW) (p < 0.001; adjusted R2 = 0.303). Deduced from this correlation, theoretical contrast dosing in grams of Iodine (g I) can be calculated: g I = 0.502 × TBW for non-steatotic livers and g I = 0.658 × TBW for steatotic livers. Objective and subjective enhancement during CT portal phase were significantly lower in steatotic livers compared to non-steatotic livers, which may have consequences for detectability and contrast dosing.

Lipid Profile and Hepatic Fat Content Measured by 1H MR Spectroscopy in Patients before and after Liver Transplantation.

Increased hepatic fat content (HFC) is a hallmark of non-alcoholic fatty liver (NAFL) disease, a common condition in liver transplant recipients. Proton MR spectroscopy (1H MRS) and MR imaging-based proton density fat fraction as the only diagnosis modality enable precise non-invasive measurement of HFC and, also, fatty acid profiles in vivo. Using 1H MRS at 3T, we examined 47 liver transplantation candidates and 101 liver graft recipients. A point-resolved spectroscopy sequence was used to calculate the steatosis grade along with the saturated, unsaturated and polyunsaturated fractions of fatty acids in the liver. The steatosis grade measured by MRS was compared with the histological steatosis grade. HFC, represented by fat fraction values, is adept at distinguishing non-alcoholic steatohepatitis (NASH), NAFL and non-steatotic liver transplant patients. Relative hepatic lipid saturation increases while unsaturation decreases in response to increased HFC. Additionally, relative hepatic lipid saturation increases while unsaturation and polyunsaturation both decrease in liver recipients with histologically proven post-transplant NASH or NAFL compared to non-steatotic patients. HFC, measured by in vivo 1H MRS, correlated well with histological results. 1H MRS is a simple and fast method for in vivo analysis of HFC and its composition. It provides non-invasive support for NAFL and NASH diagnoses.