Extrahepatic organs in the development of non-alcoholic fatty liver disease in liver transplant patients

Background and ObjectiveNon-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients who undergo liver transplantation (LT). Whereas there is huge data on NAFLD, little is known about NAFLD in LT. In this review, we aim to explore extrahepatic organs and their potential mechanisms in the development of NAFLD in LT patients and discuss current limitations in preclinical and clinical scenarios with suggestions for future study.MethodsThe following keywords, such as NAFLD, NASH, liver transplant, therapy, pathogenesis and biomarkers, were set for literature retrieval. The articles which were published articles in English till 25th June 2020 in PubMed database were included, and there is no limit for the study design type.Key Content and FindingsFollowing LT, there are significant shifts in the microbiota and farnesoid X receptor may be a potential therapeutic target for NAFLD in LT settings. The roles of probiotics and diet on NALFD remain inconclusive in LT background. Nevertheless, the adipokines and cytokines disorder and local insulin resistance of adipose tissue may contribute to NAFLD process. Bariatric surgeries are promising in controlling de novo and recurrent NAFLD with significant reduction in abdominal adipose tissue, despite the optimal timing is inconclusive in LT cases. Furthermore, circumstantial evidence indicates that miRNA-33a may function as a mediator bridging sarcopenia and NAFLD of post-LT. β-Hydroxy-β-Methyl-Butyrate treatment could improve muscle status in graft recipients and shows protective potential for NAFLD in LT settings.ConclusionsGut, adipose tissue and muscle are intricately intertwined in promoting NAFLD in LT cases. Further animal studies are needed to deepen our understanding of mechanisms in multi-organ crosstalk. High quality clinical trials are warrant for making guidelines and developing management strategies on NAFLD after LT.     

A novel radiomics signature based on T2-weighted imaging accurately predicts hepatic inflammation in individuals with biopsy-proven nonalcoholic fatty liver disease: a derivation and independent validation study

BackgroundCurrently, there are no effective methods for assessing hepatic inflammation without resorting to histological examination of liver tissue obtained by biopsy. T2-weighted images (T2WI) are routinely obtained from liver magnetic resonance imaging (MRI) scan sequences. We aimed to establish a radiomics signature based on T2WI (T2-RS) for assessment of hepatic inflammation in people with nonalcoholic fatty liver disease (NAFLD).MethodsA total of 203 individuals with biopsy-confirmed NAFLD from two independent Chinese cohorts with liver MRI examination were enrolled in this study. The hepatic inflammatory activity score (IAS) was calculated by the unweighted sum of the histologic scores for lobular inflammation and ballooning. One thousand and thirty-two radiomics features were extracted from the localized region of interest (ROI) in the right liver lobe of T2WI and, subsequently, selected by minimum redundancy maximum relevance and least absolute shrinkage and selection operator (LASSO) methods. The T2-RS was calculated by adding the selected features weighted by their coefficients.ResultsEighteen radiomics features from Laplacian of Gaussian, wavelet, and original images were selected for establishing T2-RS. The T2-RS value differed significantly between groups with increasing grades of hepatic inflammation (P<0.01). The T2-RS yielded an area under the receiver operating characteristic (ROC) curve (AUROC) of 0.80 [95% confidence interval (CI): 0.71–0.89] for predicting hepatic inflammation in the training cohort with excellent calibration. The AUROCs of T2-RS in the internal cohort and external validation cohorts were 0.77 (0.61–0.93) and 0.75 (0.63–0.84), respectively.ConclusionsThe T2-RS derived from radiomics analysis of T2WI shows promising utility for predicting hepatic inflammation in individuals with NAFLD.     

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

Background

Plant-based intravenous lipid emulsions have been shown to contribute to parenteral nutrition-associated liver disease (PNALD). There is mounting evidence that fish oil-based emulsions may prevent this liver injury. This study compares 5 emulsions with different fat compositions and their effect on hepatic steatosis, one of the first hits in PNALD.

Methods

C57BL/6J mice were placed on a fat-free diet and randomized into 5 equal groups. Each group received one of the commercially available intravenous lipid emulsions (Intralipid [Baxter/Fresenius Kabi, Deerfield, Ill], Liposyn II [Hospira Inc, Lake Forest, Ill], ClinOleic [Baxter/Clintec Parenteral SA, Cedex, France], SMOFlipid [Fresenius Kabi, Bad Homburg, Germany], or Omegaven [Fresenius Kabi Deutschland GmbH]) or normal saline. Liver enzymes, degree of steatosis, and fatty acid compositions were analyzed after 19 days.

Results

Intralipid, Liposyn II, ClinOleic, and SMOFlipid groups all demonstrated moderate steatosis with hepatic fat contents of 17.4%, 21.9%, 22.5%, and 12.6%, respectively. Omegaven mice, however, had normal livers. Saline control mice developed biochemical evidence of essential fatty acid deficiency (EFAD). Lipid supplementation with Intralipid, Liposyn II, and Omegaven prevented the onset of biochemical EFAD, whereas administration of ClinOleic and SMOFlipid did not.

Conclusion

The fish oil-based lipid emulsion Omegaven prevented hepatic steatosis and EFAD in this murine model. ω-3 fatty acids may be efficacious in preventing PNALD and should be explored in the development of novel lipid emulsions.     

肝移植治疗非酒精性脂肪性肝病的研究现状

肝移植是治疗非酒精性脂肪性肝病（NAFLD）导致的相关终末期肝病的最有效手段。但是由于肥胖、代谢综合征等不良因素的影响,肝移植术后NAFLD的复发率很高。近年来,国内、外对NAFLD相关终末期肝病肝移植取得了一定的治疗进展。本文从NAFLD及肝移植治疗NAFLD等方面的研究进展进行综述。     

Effects of cholecalciferol and calcium on experimental hepatic osteodystrophy in rats

To investigate cholecalciferol (vitamin D) metabolism disorders in hepatic osteodystrophy (HOD) and the effects of vitamin D, its metabolites, and calcium (Ca) on HOD, an experimental HOD model in rats was developed using carbon tetrachloride. In the serum level of 25-hydroxycholecalciferol, 1,25-dihydroxycholecalciferol, and 24R,25-dihydroxycholecalciferol, there were no significant differences between normal and control cirrhotic rats. Vitamin D supplementation significantly inhibited the atrophy of intestinal villi, reduction of bone calcium content, elevation of bone resorption, reduction of osteoid volume, and reduction of bone volume. Ca supplementation significantly increased the serum free Ca index and inhibited the elevation of bone resorption, the reduction of bone ash and Ca content, and the reduction of bone volume. This experimental study demonstrates that: (1) no marked vitamin D hydroxylation disorder was found in HOD; (2) vitamin D supplementation was effective in inhibiting HOD; and (3) sufficient Ca supplementation was also effective in inhibiting HOD.A portion of this work was presented at the 13th Annual Meeting of the Japanese Society for Bone and Mineral Research, July 1995, Fukuoka, Japan.     

Utility of transient elastography (fibroscan) and impact of bariatric surgery on nonalcoholic fatty liver disease (NAFLD) in morbidly obese patients

Background

Controlled attenuation parameter (CAP) is a novel, noninvasive technique for assessing hepatic steatosis. However, its role in morbidly obese individuals is unclear. The effect of bariatric surgery on inflammation and fibrosis needs to be explored.

Liver tissue microbiota in nonalcoholic liver disease: a change in the paradigm of host-bacterial interactions

Nonalcoholic fatty liver disease (NAFLD) pathogenesis is explained by the complex relationship among diet and lifestyle-predisposing factors, the genetic variance of the nuclear and mitochondrial genome, associated phenotypic traits, and the yet not fully explored interactions with epigenetic and other environmental factors, including the microbiome. Despite the wealth of knowledge gained from molecular and genome-wide investigations in patients with NAFLD, the precise mechanisms that explain the variability of the histological phenotypes are not fully understood. Earlier studies of the gut microbiota in patients with NAFLD and nonalcoholic steatohepatitis (NASH) provided clues on the role of the fecal microbiome in the disease pathogenesis. Nevertheless, the composition of the gut microbiota does not fully explain tissue-specific mechanisms associated with the degree of disease severity, including liver inflammation, ballooning of hepatocytes, and fibrosis. The liver acts as a key filtration system of the whole body by receiving blood from the hepatic artery and the portal vein. Therefore, not only microbes would become entrapped in the complex liver anatomy but, more importantly, bacterial derived products that are likely to be potentially powerful stimuli for initiating the inflammatory response. Hence, the study of liver tissue microbiota offers the opportunity of changing the paradigm of host-NAFLD-microbial interactions from a “gut-centric” to a “liver-centric” approach. Here, we highlight the evidence on the role of liver tissue bacterial DNA in the biology of NAFLD and NASH. Besides, we provide evidence of metagenomic findings that can serve as the seed of further hypothesis-raising studies as well as can be leveraged to discover novel therapeutic targets.     

Combined non-alcoholic fatty liver disease and type 2 diabetes in severely obese patients—medium term effects of sleeve gastrectomy versus Roux-en-Y-gastric bypass on disease markers

BackgroundWe aimed to evaluate the medium-term efficacy of sleeve gastrectomy (SG) vs. Roux-en-Y gastric bypass (RYGB) on remission of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM).MethodsWe identified severely obese patients [body mass index (BMI) >35 kg/m²] with NAFLD (as defined by the Longitudinal Assessment of Bariatric Surgery Study) and T2DM (as defined by the American Association of Clinical Endocrinologists and the American College of Endocrinology) who underwent SG or RYGB in a single university surgical centre. The cohorts were match-paired and data were analysed after at least 3 years of follow up. The key outcomes measured were: (I) the improvement of liver function tests and NAFLD markers; (II) glycemic control and insulin resistance.ResultsNinety-six patients were investigated; 44 (45.8%) were women. The mean pre-operative BMI was 45.2 kg/m² in the SG and 42.0 kg/m² in the RYGB group. SG and RYGB both significantly reduced serum liver enzyme concentrations. NAFLD markers resolved 2 years after SG in all patients. In contrast, only 78% and 80% of patients achieved remission of NAFLD 2 and 3 years after RYBG respectively. Both procedures resulted in comparable rates of remission of T2DM.ConclusionsBariatric surgery with SG may be preferable to RYGB for obese patients with NAFLD and T2DM based on the rates of remission of markers of these co-morbidities. However, our results need to be confirmed in prospective trials. Understanding the metabolic effects of specific bariatric surgical procedures may facilitate the development of a personalised approach to weight-loss surgery.