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Challenges in Nonalcoholic Steatohepatitis
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Challenges in Nonalcoholic Steatohepatitis

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Gastroenterology & Hepatopancreatobiliary Medicine".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 68152

Special Issue Editors

Prof. Dr. Lise Lotte Gluud

E-Mail Website
Guest Editor
Gastro Unit, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
Interests: non-alcoholic steatohepatitis; non-alcoholic fatty liver disease; cirrhosis; biomarkers; clinical trials
Dr. Nicolai Jacob Wewer Albrechtsen

E-Mail Website
Guest Editor
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Interests: non-alcoholic steatohepatitis; non-alcoholic fatty liver disease; cirrhosis; biomarkers; proteomics

Special Issue Information

Dear Colleagues,

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is closely linked with obesity and type 2 diabetes, and the incidence is increasing rapidly. NAFLD is a condition which ranges from simple steatosis to the more aggressive disease non-alcoholic steatohepatitis (NASH) and eventually to cirrhosis and hepatocellular carcinoma. The economic and societal burden of NAFLD is considerable, and reliable biomarkers as well as effective treatments are urgently needed.

The prevalence of NAFLD parallels that of metabolic syndrome. Most patients who are diagnosed are middle aged, whereas the gender distribution is debated. Ethnic differences have been identified, and genetic as well as socio-economic factors are important. The outcome of NAFLD has been studied, but the progression varies considerably and the prediction of the course of the disease for individual patients is difficult. Prospective data are limited, as are larger population studies with valid diagnostic criteria. Most patients with NAFLD are asymptomatic, and the diagnosis is made following incidental findings. The diagnosis is often made based on a combination of diagnostic imaging and biochemical changes combined with the exclusion of other causes of steatosis. The gold standard is histological assessment of liver tissue, which is unsuitable for larger population studies. Several markers and clinical diagnostic scores have been suggested, but the available biomarkers cannot give an accurate diagnosis when used alone.

This Issue will identify the gaps in the diagnosis and management of NAFLD based on a combination of original research and review papers.

Topics will include

  • The epidemiology of NAFLD;
  • The role of genetics in the development of NAFLD;
  • Biochemical changes associated with NAFLD;
  • Diagnostic approaches including omics biomarkers;
  • Interventions for NAFLD.
Prof. Lise Lotte Gluud
Dr. Nicolai Jacob Wewer Albrechtsen
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • non-alcoholic fatty liver disease
  • genetics
  • epidemiology
  • proteomics
  • transcriptomics
  • oxidative stress
  • treatment

Published Papers (16 papers)

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Research

Jump to: Review

14 pages, 1556 KiB  
Article
Predictive Power of Tissue and Circulating Biomarkers for the Severity of Biopsy-Validated Chronic Liver Diseases
by Guido Bocci, Paola Orlandi, Maria Laura Manca, Chiara Rossi, Antonio Salvati, Maurizia Rossana Brunetto and Anna Solini
J. Clin. Med. 2022, 11(20), 5985; https://doi.org/10.3390/jcm11205985 - 11 Oct 2022
Cited by 1 | Viewed by 1199
Abstract
Background: Although liver biopsy remains the gold standard for the diagnosis and the monitoring of liver disease, non-invasive biomarkers have been recently suggested to predict liver disease severity, progression, and response to therapy. We investigated multiple tissue and circulating markers of angiogenesis in [...] Read more.
Background: Although liver biopsy remains the gold standard for the diagnosis and the monitoring of liver disease, non-invasive biomarkers have been recently suggested to predict liver disease severity, progression, and response to therapy. We investigated multiple tissue and circulating markers of angiogenesis in predicting the severity of biopsy-validated chronic liver diseases in patients with chronic hepatitis C virus (HCV) and in NAFLD/NASH patients. Methods: We studied samples from forty-six patients with HCV and/or NAFLD who underwent liver biopsy, liver ultrasonography, and liver stiffness measurement. Ishak and Brunt scores were calculated. Expression of selective genes and luminex analyses of 17 different circulating pro-angiogenic factors were performed. Results: The phenotype of NAFLD/NASH or HCV subjects was similar, except for insulin, which was expressed at higher levels in NAFLD/NASH patients. A Mann–Whitney test showed significant differences for the circulating levels of HB-EGF and for follistatin between HCV and NAFLD/NASH patients. In HCV patients, we found an inverse correlation between disease stage and BMP-9 and VEGF-A circulating levels, while in NASH/NAFLD direct correlations between stage and BMP-9 and VEGF-A circulating levels were noted. The K-means algorithm divided HCV and NASH/NAFLD patients in two clusters with significant differences between them. Logistic regression models showed a positive relationship with BMP-9 levels for NASH/NAFLD and with HB-EGF circulating concentrations for HCV. ROC analysis showed for BMP-9 > 1188 pg/mL a worse disease in NASH/NAFLD, whereas for HB-EGF < 61 pg/mL a higher severity of disease in HCV. Conclusion: Our data show that circulating biomarker profiles can identify the severity of chronic liver disease of NAFLD/NASH or HCV origin. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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9 pages, 403 KiB  
Article
Clinical Progression of Metabolic-Associated Fatty Liver Disease Is Rare in a Danish Tertiary Liver Center
by Tea Lund Laursen, Mikkel Breinholt Kjær, Louise Kristensen and Henning Grønbæk
J. Clin. Med. 2022, 11(9), 2271; https://doi.org/10.3390/jcm11092271 - 19 Apr 2022
Cited by 1 | Viewed by 1732
Abstract
Data concerning non-invasive discrimination of simple steatosis from steatohepatitis in metabolic-associated fatty liver disease (MAFLD) and risk of disease progression in patients with MAFLD are conflicting. We aimed to investigate these factors in an MAFLD cohort at a Danish tertiary liver centre. We [...] Read more.
Data concerning non-invasive discrimination of simple steatosis from steatohepatitis in metabolic-associated fatty liver disease (MAFLD) and risk of disease progression in patients with MAFLD are conflicting. We aimed to investigate these factors in an MAFLD cohort at a Danish tertiary liver centre. We retrospectively assessed 129 patients with biopsy-proven MAFLD. Patients were divided according to the presence of simple steatosis or steatohepatitis in liver biopsies. Histological and clinical progression were assessed during follow-up. Patients with steatohepatitis had higher BMIs, liver stiffness, HbA1c and soluble (sCD163) and were more prone to have metabolic syndrome at baseline compared with simple steatosis patients. Of the 129 patients, 31 had a follow-up biopsy after a median of 287 days; simple steatosis progressed to steatohepatitis in 7 cases, while 2 regressed. Twenty patients had the same fibrosis stage according to the follow-up biopsy, seven progressed and four regressed. Only 14 patients progressed clinically (median follow-up time was 3.8 years). Clinical progression was associated with female sex, high creatinine, high sCD163 and disease severity in the diagnostic liver biopsy. Steatohepatitis was associated with metabolic and inflammatory parameters including fibroscan. Disease progression was seen in only 11% of cases and was mainly related to more severe histological disease at baseline. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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10 pages, 1089 KiB  
Article
Association of Body Composition and Sarcopenia with NASH in Obese Patients
by Sophia Marie-Therese Schmitz, Lena Schooren, Andreas Kroh, Alexander Koch, Christine Stier, Ulf Peter Neumann, Tom Florian Ulmer and Patrick Hamid Alizai
J. Clin. Med. 2021, 10(15), 3445; https://doi.org/10.3390/jcm10153445 - 3 Aug 2021
Cited by 11 | Viewed by 2618
Abstract
Obese patients often suffer from sarcopenia or sarcopenic obesity (SO) that can trigger inflammatory diseases including non-alcoholic steatohepatitis (NASH). Sarcopenia and SO can be diagnosed through measuring parameters of body composition such as skeletal muscle mass (SMM), skeletal muscle index (SMI) and fat [...] Read more.
Obese patients often suffer from sarcopenia or sarcopenic obesity (SO) that can trigger inflammatory diseases including non-alcoholic steatohepatitis (NASH). Sarcopenia and SO can be diagnosed through measuring parameters of body composition such as skeletal muscle mass (SMM), skeletal muscle index (SMI) and fat mass (FM) obtained by bioelectrical impedance analysis (BIA). The aim of this study was to assess the relationship of body composition and NASH in patients with obesity. A total of 138 patients with obesity that underwent bariatric surgery were included in this study. BIA was used to estimate body composition. A liver biopsy was taken intraoperatively and histological assessment of NASH was performed. A total of 23 patients (17%) were classified as NASH and 65 patients (47%) met the criteria for borderline NASH. Body mass index (BMI) was significantly higher in patients with NASH compared to borderline NASH and no NASH (56.3 kg/m2 vs. 51.6 kg/m2 vs. 48.6 kg/m2, p = 0.004). Concerning body composition, FM, but also SMM and SMI were significantly higher in patients with NASH (p-values 0.011, 0.005 and 0.006, resp.). Fat mass index (FMI) and weight-adjusted skeletal muscle index (SMI_weight) failed to reach statistical significance (p-values 0.067 and 0.661). In patients with obesity, higher FM were associated with NASH. Contrary to expectations, SMM and SMI were also higher in patients with NASH. Therefore, higher body fat, rather than sarcopenia and SO, might be decisive for development of NASH in patients with obesity. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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9 pages, 2038 KiB  
Article
Attenuation Imaging with Ultrasound as a Novel Evaluation Method for Liver Steatosis
by Po-Ke Hsu, Li-Sha Wu, Hsu-Heng Yen, Hsiu Ping Huang, Yang-Yuan Chen, Pei-Yuan Su and Wei-Wen Su
J. Clin. Med. 2021, 10(5), 965; https://doi.org/10.3390/jcm10050965 - 2 Mar 2021
Cited by 20 | Viewed by 3837
Abstract
In recent years, ultrasound attenuation imaging (ATI) has emerged as a new method to detect liver steatosis. However, thus far, no studies have confirmed the clinical utility of this technology. Using a retrospective database analysis of 28 patients with chronic liver disease who [...] Read more.
In recent years, ultrasound attenuation imaging (ATI) has emerged as a new method to detect liver steatosis. However, thus far, no studies have confirmed the clinical utility of this technology. Using a retrospective database analysis of 28 patients with chronic liver disease who underwent ultrasound liver biopsy and ATI, we compared the presence and degree of steatosis measured by ATI with the results obtained through liver biopsy. The area under the receiver operating characteristic curve (AUROC) of the ATI for differentiating between normal and hepatic steatosis was 0.97 (95% confidence interval: 0.83–1.00). The AUROC of the ATI was 0.99 (95% confidence interval: 0.86–1.00) in grade ≥2 liver steatosis and 0.97 (95% confidence interval: 0.82–1.00) in grade 3. ATI showed good consistency and accuracy for the steatosis grading of liver biopsy. Therefore, ATI represents a novel diagnostic measurement to support the diagnosis of liver steatosis in non-invasive clinical practice. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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8 pages, 242 KiB  
Article
Referral Patterns for Patients with Nonalcoholic Fatty Liver Disease
by Elias Badal Rashu, Mikkel Parsberg Werge, Liv Eline Hetland, Anders Ellekaer Junker, Majken Karoline Jensen and Lise Lotte Gluud
J. Clin. Med. 2021, 10(3), 404; https://doi.org/10.3390/jcm10030404 - 21 Jan 2021
Cited by 1 | Viewed by 1856
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing. This study evaluates the referral pattern of patients with NAFLD. A cohort study evaluating all patients with NAFLD referred to a single Gastroenterology Department from January 2017 to June 2020. Electronic patient [...] Read more.
The incidence of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing. This study evaluates the referral pattern of patients with NAFLD. A cohort study evaluating all patients with NAFLD referred to a single Gastroenterology Department from January 2017 to June 2020. Electronic patient referral letters were reviewed, and patients with NAFLD were diagnosed using standardized tests as part of a prospective cohort study. Predictors of nonalcoholic steatohepatitis (NASH) with significant (≥F2) fibrosis were evaluated in logistic regression analyses. In total, 323 (18.6%) of 1735 patients referred to the Gastro Unit during the study period were diagnosed with NAFLD. Patients were referred from general practitioners (62.5%) or other hospital departments (37.5%). Most referral letters included information suggesting a possible diagnosis of NAFLD (patient history, blood tests, or diagnostic imaging) or used the nonspecific general diagnosis suspected disease (Z.038). Out of 110 patients referred for a liver biopsy, 71 (22%) had NASH with significant fibrosis (F2 n = 39, F3 n = 19, F4 n = 13). Thirty-nine of these patients were referred from the primary sector. A logistic regression analysis (adjusted for age and gender) including all 323 patients showed that type 2 diabetes was the only significant independent predictor of NASH with fibrosis. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
11 pages, 485 KiB  
Article
Associations of HDL Subspecies Defined by ApoC3 with Non-Alcoholic Fatty Liver Disease: The Multi-Ethnic Study of Atherosclerosis
by Jakub Morze, Manja Koch, Sarah A. Aroner, Matthew Budoff, Robyn L. McClelland, Kenneth J. Mukamal and Majken K. Jensen
J. Clin. Med. 2020, 9(11), 3522; https://doi.org/10.3390/jcm9113522 - 31 Oct 2020
Cited by 8 | Viewed by 2249
Abstract
Previously, we reported that inverse associations of high-density lipoprotein (HDL) with cardiovascular disease and diabetes were only observed for HDL that lacked the pro-inflammatory protein apolipoprotein C3 (apoC3). To provide further insight into the cardiometabolic properties of HDL subspecies defined by the presence [...] Read more.
Previously, we reported that inverse associations of high-density lipoprotein (HDL) with cardiovascular disease and diabetes were only observed for HDL that lacked the pro-inflammatory protein apolipoprotein C3 (apoC3). To provide further insight into the cardiometabolic properties of HDL subspecies defined by the presence or absence of apoC3, we aimed to examine these subspecies with liver fat content and non-alcoholic fatty liver disease (NAFLD). We investigated cross-sectional associations between ELISA-measured plasma levels of apoA1 in HDL that contained or lacked apoC3 and computed tomography-determined liver fat content and NAFLD (<51 HU) at baseline (2000–2002) among 5007 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) without heavy alcohol consumption (>14 drinks/week in men and >7 drinks/week in women). In multivariable-adjusted regression models, apoA1 in HDL that contained or lacked apoC3 was differentially associated with liver fat content (Pheterogeneity = 0.048). While apoA1 in HDL that lacked apoC3 was inversely associated with liver fat content (Ptrend < 0.0001), apoA1 in HDL that contained apoC3 was not statistically significantly associated with liver fat content (Ptrend = 0.57). Higher apoA1 in HDL that lacked apoC3 was related to a lower prevalence of NAFLD (OR per SD: 0.80; 95% CI: 0.72, 0.89), whereas no association was found for apoA1 in HDL that contained apoC3 (OR per SD: 0.95; 95% CI: 0.85, 1.05; Pheterogeneity = 0.09). Higher apoA1 in HDL that lacked apoC3 was associated with less liver fat content and a lower prevalence of NAFLD. This finding extends the inverse association of HDL lacking apoC3 from cardiovascular disease to NAFLD. Lack of biopsy-proven hepatic steatosis and fibrosis data requires the replication of our study in further studies. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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12 pages, 2398 KiB  
Article
Baseline Presence of NAFLD Predicts Weight Loss after Gastric Bypass Surgery for Morbid Obesity
by Karl Peter Rheinwalt, Uta Drebber, Robert Schierwagen, Sabine Klein, Ulf Peter Neumann, Tom Florian Ulmer, Andreas Plamper, Andreas Kroh, Sandra Schipper, Margarete Odenthal, Frank Erhard Uschner, Philipp Lingohr, Jonel Trebicka and Maximilian Joseph Brol
J. Clin. Med. 2020, 9(11), 3430; https://doi.org/10.3390/jcm9113430 - 26 Oct 2020
Cited by 13 | Viewed by 2366
Abstract
Background. Bariatric surgery is a widely used treatment for morbid obesity. Prediction of postoperative weight loss currently relies on prediction models, which mostly overestimate patients’ weight loss. Data about the influence of Non-alcoholic fatty liver disease (NAFLD) on early postoperative weight loss are [...] Read more.
Background. Bariatric surgery is a widely used treatment for morbid obesity. Prediction of postoperative weight loss currently relies on prediction models, which mostly overestimate patients’ weight loss. Data about the influence of Non-alcoholic fatty liver disease (NAFLD) on early postoperative weight loss are scarce. Methods. This prospective, single-center cohort study included 143 patients receiving laparoscopic gastric bypass surgery (One Anastomosis-Mini Gastric Bypass (OAGB-MGB) or Roux-en-Y Gastric Bypass (RYGB)). Liver biopsies were acquired at surgery. NAFLD activity score (NAS) assigned patients to “No NAFLD”, “NAFL” or “NASH”. Follow up data were collected at 3, 6 and 12 months. Results. In total, 49.7% of patients had NASH, while 41.3% had NAFL. Compared with the No NAFLD group, NAFL and NASH showed higher body-mass-index (BMI) at follow-up (6 months: 31.0 kg/m2 vs. 36.8 kg/m2 and 36.1 kg/m2, 12 months: 27.0 kg/m2 vs. 34.4 and 32.8 kg/m2) and lower percentage of total body weight loss (%TBWL): (6 months: 27.1% vs. 23.3% and 24.4%; 12 months: 38.5% vs. 30.1 and 32.6%). Linear regression of NAS points significantly predicts percentage of excessive weight loss (%EWL) after 6 months (Cologne-weight-loss-prediction-score). Conclusions. Histopathological presence of NAFLD might lead to inferior postoperative weight reduction after gastric bypass surgery. The mechanisms underlying this observation should be further studied. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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14 pages, 633 KiB  
Article
One Year’s Treatment with the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide Decreases Hepatic Fat Content in Women with Nonalcoholic Fatty Liver Disease and Prior Gestational Diabetes Mellitus in a Randomized, Placebo-Controlled Trial
by Louise Vedtofte, Emilie Bahne, Signe Foghsgaard, Jonatan I. Bagger, Camilla Andreasen, Charlotte Strandberg, Peter M. Gørtz, Jens J. Holst, Henning Grønbæk, Jens A. Svare, Tine D. Clausen, Elisabeth R. Mathiesen, Peter Damm, Lise L. Gluud, Filip K. Knop and Tina Vilsbøll
J. Clin. Med. 2020, 9(10), 3213; https://doi.org/10.3390/jcm9103213 - 6 Oct 2020
Cited by 16 | Viewed by 2819
Abstract
Prior gestational diabetes mellitus (pGDM) is associated with increased risk of nonalcoholic fatty liver disease (NAFLD). Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists has shown beneficial effects in NAFLD patients. We evaluated the effect of the GLP-1 analogue liraglutide on NAFLD features [...] Read more.
Prior gestational diabetes mellitus (pGDM) is associated with increased risk of nonalcoholic fatty liver disease (NAFLD). Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists has shown beneficial effects in NAFLD patients. We evaluated the effect of the GLP-1 analogue liraglutide on NAFLD features in women with pGDM. Eighty-two overweight/obese, nondiabetic women with pGDM were included. We performed abdominal ultrasound, transient elastography with controlled attenuation parameter (CAP), and blood sampling at baseline and after 1 year. Thirty-seven women were randomized to liraglutide (1.8 mg once-daily) and 45 to placebo. Based on the ultrasound scan, 18 women (22%) had ultrasound-verified NAFLD at baseline and of these, 10 (56%) received liraglutide treatment. After 1 year, eight participants no longer had steatosis, four in each treatment group. The number of participants who developed NAFLD was similar in the two treatment groups; five in the liraglutide group and six in the placebo group (p = 0.74). Compared to placebo, liraglutide reduced the CAP-assessed intrahepatic fat content (−28 (−44;−11) vs. 2 (−13;18) dB/m, p < 0.01) and body weight (−4.7 (−6.4;−2.9) vs. −1.4 (−3;0.3) kg, p < 0.01). One-year’s liraglutide treatment had no effect on the presence of ultrasound-diagnosed NAFLD in overweight/obese nondiabetic women with pGDM, but reduced body weight and steatosis assessed by transient elastography with CAP. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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Review

Jump to: Research

22 pages, 1317 KiB  
Review
Defining NASH from a Multi-Omics Systems Biology Perspective
by Lili Niu, Karolina Sulek, Catherine G. Vasilopoulou, Alberto Santos, Nicolai J. Wewer Albrechtsen, Simon Rasmussen, Florian Meier and Matthias Mann
J. Clin. Med. 2021, 10(20), 4673; https://doi.org/10.3390/jcm10204673 - 12 Oct 2021
Cited by 8 | Viewed by 5829
Abstract
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease affecting up to 6.5% of the general population. There is no simple definition of NASH, and the molecular mechanism underlying disease pathogenesis remains elusive. Studies applying single omics technologies have enabled a better understanding of [...] Read more.
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease affecting up to 6.5% of the general population. There is no simple definition of NASH, and the molecular mechanism underlying disease pathogenesis remains elusive. Studies applying single omics technologies have enabled a better understanding of the molecular profiles associated with steatosis and hepatic inflammation—the commonly accepted histologic features for diagnosing NASH, as well as the discovery of novel candidate biomarkers. Multi-omics analysis holds great potential to uncover new insights into disease mechanism through integrating multiple layers of molecular information. Despite the technical and computational challenges associated with such efforts, a few pioneering studies have successfully applied multi-omics technologies to investigate NASH. Here, we review the most recent technological developments in mass spectrometry (MS)-based proteomics, metabolomics, and lipidomics. We summarize multi-omics studies and emerging omics biomarkers in NASH and highlight the biological insights gained through these integrated analyses. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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20 pages, 1209 KiB  
Review
The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease
by Mikkel Parsberg Werge, Adrian McCann, Elisabeth Douglas Galsgaard, Dorte Holst, Anne Bugge, Nicolai J. Wewer Albrechtsen and Lise Lotte Gluud
J. Clin. Med. 2021, 10(5), 1081; https://doi.org/10.3390/jcm10051081 - 5 Mar 2021
Cited by 32 | Viewed by 11515
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a [...] Read more.
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H2S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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15 pages, 1535 KiB  
Review
The Role of Diagnostic Biomarkers, Omics Strategies, and Single-Cell Sequencing for Nonalcoholic Fatty Liver Disease in Severely Obese Patients
by Charlotte W. Wernberg, Kim Ravnskjaer, Mette M. Lauridsen and Maja Thiele
J. Clin. Med. 2021, 10(5), 930; https://doi.org/10.3390/jcm10050930 - 1 Mar 2021
Cited by 6 | Viewed by 5643
Abstract
Liver disease due to metabolic dysfunction constitute a worldwide growing health issue. Severe obesity is a particularly strong risk factor for non-alcoholic fatty liver disease, which affects up to 93% of these patients. Current diagnostic markers focus on the detection of advanced fibrosis [...] Read more.
Liver disease due to metabolic dysfunction constitute a worldwide growing health issue. Severe obesity is a particularly strong risk factor for non-alcoholic fatty liver disease, which affects up to 93% of these patients. Current diagnostic markers focus on the detection of advanced fibrosis as the major predictor of liver-related morbidity and mortality. The most accurate diagnostic tools use elastography to measure liver stiffness, with diagnostic accuracies similar in normal-weight and severely obese patients. The effectiveness of elastography tools are however hampered by limitations to equipment and measurement quality in patients with very large abdominal circumference and subcutaneous fat. Blood-based biomarkers are therefore attractive, but those available to date have only moderate diagnostic accuracy. Ongoing technological advances in omics technologies such as genomics, transcriptomics, and proteomics hold great promise for discovery of biomarkers and increased pathophysiological understanding of non-alcoholic liver disease and steatohepatitis. Very recent developments have allowed for single-cell sequencing and cell-type resolution of gene expression and function. In the near future, we will therefore likely see a multitude of breakthrough biomarkers, developed from a deepened understanding of the biological function of individual cell types in the healthy and injured liver. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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20 pages, 884 KiB  
Review
Cognitive Dysfunction in Non-Alcoholic Fatty Liver Disease—Current Knowledge, Mechanisms and Perspectives
by Kristoffer Kjærgaard, Anne Catrine Daugaard Mikkelsen, Charlotte Wilhelmina Wernberg, Lea Ladegaard Grønkjær, Peter Lykke Eriksen, Malene Flensborg Damholdt, Rajeshwar Prosad Mookerjee, Hendrik Vilstrup, Mette Munk Lauridsen and Karen Louise Thomsen
J. Clin. Med. 2021, 10(4), 673; https://doi.org/10.3390/jcm10040673 - 9 Feb 2021
Cited by 52 | Viewed by 6233
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as the hepatic component of the metabolic syndrome and now seemingly affects one-fourth of the world population. Features associated with NAFLD and the metabolic syndrome have frequently been linked to cognitive dysfunction, i.e. systemic inflammation, vascular [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) has emerged as the hepatic component of the metabolic syndrome and now seemingly affects one-fourth of the world population. Features associated with NAFLD and the metabolic syndrome have frequently been linked to cognitive dysfunction, i.e. systemic inflammation, vascular dysfunction, and sleep apnoea. However, emerging evidence suggests that NAFLD may be a cause of cognitive dysfunction independent of these factors. NAFLD in addition exhibits dysbiosis of the gut microbiota and impaired urea cycle function, favouring systemic ammonia accumulation and further promotes systemic inflammation. Such disruption of the gut–liver–brain axis is essential in the pathogenesis of hepatic encephalopathy, the neuropsychiatric syndrome associated with progressive liver disease. Considering the growing burden of NAFLD, the morbidity from cognitive impairment is expected to have huge societal and economic impact. The present paper provides a review of the available evidence for cognitive dysfunction in NAFLD and outlines its possible mechanisms. Moreover, the clinical challenges of characterizing and diagnosing cognitive dysfunction in NAFLD are discussed. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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19 pages, 3563 KiB  
Review
Metabolic Imaging in Non-Alcoholic Fatty Liver Disease: Applications of Magnetic Resonance Spectroscopy
by Prarthana Thiagarajan, Stephen J. Bawden and Guruprasad P. Aithal
J. Clin. Med. 2021, 10(4), 632; https://doi.org/10.3390/jcm10040632 - 7 Feb 2021
Cited by 7 | Viewed by 2858
Abstract
Non-alcoholic fatty liver disease (NAFLD) is poised to dominate the landscape of clinical hepatology in the 21st century. Its complex, interdependent aetiologies, non-linear disease progression and uncertain natural history have presented great challenges to the development of effective therapies. Progress will require an [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is poised to dominate the landscape of clinical hepatology in the 21st century. Its complex, interdependent aetiologies, non-linear disease progression and uncertain natural history have presented great challenges to the development of effective therapies. Progress will require an integrated approach to uncover molecular mediators, key pathogenic milestones and response to intervention at the metabolic level. The advent of precision imaging has yielded unprecedented insights into these processes. Quantitative imaging biomarkers such as magnetic resonance imaging (MRI), spectroscopy (MRS) and elastography (MRE) present robust, powerful tools with which to probe NAFLD metabolism and fibrogenesis non-invasively, in real time. Specific advantages of MRS include the ability to quantify static metabolite concentrations as well as dynamic substrate flux in vivo. Thus, a vast range of key metabolic events in the natural history of NAFLD can be explored using MRS. Here, we provide an overview of MRS for the clinician, as well as key pathways exploitable by MRS in vivo. Development, optimisation and validation of multinuclear MRS, in combination with other quantitative imaging techniques, may ultimately provide a robust, non-invasive alternative to liver biopsy for observational and longitudinal studies. Through enabling deeper insight into inflammatory and fibrogenic cascades, MRS may facilitate identification of novel therapeutic targets and clinically meaningful endpoints in NAFLD. Its widespread use in future could conceivably accelerate study design, data acquisition and availability of disease-modifying therapies at a population level. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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13 pages, 844 KiB  
Review
The Role of Hepatic Fat Accumulation in Glucose and Insulin Homeostasis—Dysregulation by the Liver
by Amalie London, Anne-Marie Lundsgaard, Bente Kiens and Kirstine Nyvold Bojsen-Møller
J. Clin. Med. 2021, 10(3), 390; https://doi.org/10.3390/jcm10030390 - 20 Jan 2021
Cited by 11 | Viewed by 4563
Abstract
Accumulation of hepatic triacylglycerol (TG) is associated with obesity and metabolic syndrome, which are important pathogenic factors in the development of type 2 diabetes. In this narrative review, we summarize the effects of hepatic TG accumulation on hepatic glucose and insulin metabolism and [...] Read more.
Accumulation of hepatic triacylglycerol (TG) is associated with obesity and metabolic syndrome, which are important pathogenic factors in the development of type 2 diabetes. In this narrative review, we summarize the effects of hepatic TG accumulation on hepatic glucose and insulin metabolism and the underlying molecular regulation in order to highlight the importance of hepatic TG accumulation for whole-body glucose metabolism. We find that liver fat accumulation is closely linked to impaired insulin-mediated suppression of hepatic glucose production and reduced hepatic insulin clearance. The resulting systemic hyperinsulinemia has a major impact on whole-body glucose metabolism and may be an important pathogenic step in the development of type 2 diabetes. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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11 pages, 453 KiB  
Review
The Vicious Circle of Hepatic Glucagon Resistance in Non-Alcoholic Fatty Liver Disease
by Katrine D. Galsgaard
J. Clin. Med. 2020, 9(12), 4049; https://doi.org/10.3390/jcm9124049 - 15 Dec 2020
Cited by 21 | Viewed by 6381
Abstract
A key criterion for the most common chronic liver disease—non-alcoholic fatty liver disease (NAFLD)—is an intrahepatic fat content above 5% in individuals who are not using steatogenic agents or having significant alcohol intake. Subjects with NAFLD have increased plasma concentrations of glucagon, and [...] Read more.
A key criterion for the most common chronic liver disease—non-alcoholic fatty liver disease (NAFLD)—is an intrahepatic fat content above 5% in individuals who are not using steatogenic agents or having significant alcohol intake. Subjects with NAFLD have increased plasma concentrations of glucagon, and emerging evidence indicates that subjects with NAFLD may show hepatic glucagon resistance. For many years, glucagon has been thought of as the counterregulatory hormone to insulin with a primary function of increasing blood glucose concentrations and protecting against hypoglycemia. However, in recent years, glucagon has re-emerged as an important regulator of other metabolic processes including lipid and amino acid/protein metabolism. This review discusses the evidence that in NAFLD, hepatic glucagon resistance may result in a dysregulated lipid and amino acid/protein metabolism, leading to excess accumulation of fat, hyperglucagonemia, and increased oxidative stress contributing to the worsening/progression of NAFLD. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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17 pages, 2627 KiB  
Review
A Role for Gut Microbiome Fermentative Pathways in Fatty Liver Disease Progression
by Paula Iruzubieta, Juan M. Medina, Raúl Fernández-López, Javier Crespo and Fernando de la Cruz
J. Clin. Med. 2020, 9(5), 1369; https://doi.org/10.3390/jcm9051369 - 7 May 2020
Cited by 26 | Viewed by 4804
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease in which environmental and genetic factors are involved. Although the molecular mechanisms involved in NAFLD onset and progression are not completely understood, the gut microbiome (GM) is thought to play a key role in [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease in which environmental and genetic factors are involved. Although the molecular mechanisms involved in NAFLD onset and progression are not completely understood, the gut microbiome (GM) is thought to play a key role in the process, influencing multiple physiological functions. GM alterations in diversity and composition directly impact disease states with an inflammatory course, such as non-alcoholic steatohepatitis (NASH). However, how the GM influences liver disease susceptibility is largely unknown. Similarly, the impact of strategies targeting the GM for the treatment of NASH remains to be evaluated. This review provides a broad insight into the role of gut microbiota in NASH pathogenesis, as a diagnostic tool, and as a therapeutic target in this liver disease. We highlight the idea that the balance in metabolic fermentations can be key in maintaining liver homeostasis. We propose that an overabundance of alcohol-fermentation pathways in the GM may outcompete healthier, acid-producing members of the microbiota. In this way, GM ecology may precipitate a self-sustaining vicious cycle, boosting liver disease progression. Full article
(This article belongs to the Special Issue Challenges in Nonalcoholic Steatohepatitis)
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