Special Issue "Should Physicians Consider NAFLD a Primary or Secondary Disease?"

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 (10 March 2021).

Special Issue Editor

Prof. Dr. Giovanni Tarantino
E-Mail Website
Guest Editor
Department of Clinical Medicine and Surgery, University of Naples Federico II,UNINA, Naples, Italy
Interests: nonalcoholic fatty liver disease; metabolic syndrome; obesity; atherosclerosis and NAFLD; PCOS and NAFLD; HCV-related chronic hepatitis; HCV-related arthritis; therapy of liver cirrhosis; portal hypertension; hepatic encephalopathy; imaging ultrasonography of liver and spleen; psoriatic arthritis and NAFLD; cytokines in obesity
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Special Issue Information

Dear Colleagues,

Obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus (T2DM) are mostly prominent in Western societies (but are not restricted to these), and represent the well-known metabolic syndrome. Focusing on obesity, there is a great body of evidence that both genetic and environmental factors are important in its genesis and evolution. Whereas the genetic factors are still poorly understood, numerous studies have shown that particularly abdominal obesity and physical inactivity are central. Specifically, obesity is a major risk factor for the development of insulin resistance—a key factor in the etiology of the metabolic syndrome and T2DM. Obesity and insulin resistance promote the development of non-alcoholic fatty liver disease (NAFLD), which in a subset of patients can evolve in a more severe form (i.e., non-alcoholic steatohepatitis, NASH). NASH is characterized by fatty infiltration of the liver and inflammation leading to the apoptosis and necrosis of hepatocytes—features to which reparative responses follow, resulting in fibrosis. Unfortunately, research is far from completely clarifying the genesis of these diseases (NAFLD/NASH) and suggesting appropriate therapy to drastically reduce or eliminate them. Finally, there is still much debate as to whether NAFLD/NASH is a primary or secondary illness.

This Special Issue is set to gather research concerning the unknown mechanisms of these diseases and to confirm the consolidated ones with new observations.

Potential topics include but are not limited to the following:

  • Obesity-related NAFLD;
  • Non-obese NAFLD;
  • Genetic NAFLD;
  • Re-feeding NAFLD;
  • PCOS-associated NAFLD;
  • OSAS-associated NAFLD;
  • Drug-induced NAFLD (including toxic substances);
  • Juvenile NAFLD;
  • Silent NASH;
  • Is NAFLD really benign?
  • The role of metabolic syndrome in the onset and worsening of NAFLD;
  • The link between NAFLD and hepatocarcinoma;
  • Immune system involvement, with special attention to the major immune organ (i.e., spleen);
  • Chronic low-grade inflammation;
  • Adipokines, hormones, and growth factors involved in the pathogenesis of NAFLD/NASH;
  • Mitochondrial dysfunction at the basis of NAFLD;
  • The interplay between microbiome and/or virome and NAFLD;
  • Environmental factors linked to NAFLD;
  • The emerging role of MUFAs.

Prof. Dr. Giovanni Tarantino
Guest Editor

Manuscript Submission Information

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Keywords

  • Obesity- related NAFLD
  • Non obese NAFLD
  • NASH
  • Genetic NAFLD
  • Metabolic Syndrome
  • Chronic low-grade inflammation
  • Inmune system involvement
  • Adipokines (mechanisms)
  • Cytokines (mechanisms)
  • Hormones and Growth Factors (mechanisms)

Published Papers (8 papers)

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Research

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Article
Association of NAFLD and Insulin Resistance with Non Metastatic Bladder Cancer Patients: A Cross-Sectional Retrospective Study
J. Clin. Med. 2021, 10(2), 346; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10020346 - 18 Jan 2021
Cited by 7 | Viewed by 814
Abstract
Among risk factors (apart from smoking) likely involved in bladder cancer (BCa), metabolic syndrome (MS), obesity and type 2 diabetes mellitus (T2DM) have been explored with contrasting results. In spite of these studies, there is little data on the association between nonalcoholic fatty [...] Read more.
Among risk factors (apart from smoking) likely involved in bladder cancer (BCa), metabolic syndrome (MS), obesity and type 2 diabetes mellitus (T2DM) have been explored with contrasting results. In spite of these studies, there is little data on the association between nonalcoholic fatty liver disease (NAFLD), its main driver, i.e., insulin resistance (IR), and BCa. Implanting a cross-sectional retrospective study we tried to investigate both NAFLD and IR prevalence in a hospital based population of BCa patients. We studied laboratory data from 204 patients with histologically confirmed non metastatic BCa and 50 subjects with no BCa, but with bladder diseases (no Ca BD). We evaluated the presence of NAFLD by the triglycerides/glucose Index (TyG Index), using a cut-off of 0.59 and by the Aspartate Aminotransferase/Alanine Aminotransferase AST/ALT ratio. IR was assessed by the same TyG Index (cut-off 4.68) and the triglycerides/High-Density Lipoprotein HDL ratio (cut-off 2.197). The diagnosis of impaired fasting glucose (IFG), condition of prediabetes, as well as that of T2DM was assessed according to canonical guidelines. The TyG Index predicted NAFLD presence in both groups (p = 0.000), but the BCa group showed a major percentage of NAFLD cases with respect to no Ca BD group (59% versus 40%). A greater proportion of IR (47%) in BCa group than in no Ca BD one (37%) was evidenced by the TyG Index with its median value significantly different (p = 0.0092). This high rate of IR in the BCa group was confirmed by the triglycerides/HDL ratio (p = 0.02). Prediabetes and T2DM were more prevalent in the BCa group than no Ca BD group (p = 0.024). In this study a consistent NAFLD presence was found in BCa patients. This is an important comorbidity factor that deserves further consideration in prospective studies. The higher prevalence of NAFLD, IR, prediabetes and T2DM in the BCa group evidences the need that these disorders should be reckoned as adjunct factors that could impact on this cancerous disease. Full article
(This article belongs to the Special Issue Should Physicians Consider NAFLD a Primary or Secondary Disease?)
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Article
Non-Alcoholic Fatty Liver Disease Markers Associated with Fasting Serum Insulin and Urinary Albumin Excretion Independent of Fasting Plasma Glucose
J. Clin. Med. 2020, 9(10), 3161; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9103161 - 29 Sep 2020
Viewed by 616
Abstract
Objective: We examined the association between non-alcoholic fatty liver disease (NAFLD) markers and fasting serum immunoreactive insulin (FIRI) and urinary albumin excretion (UAE). Subjects and methods: This study comprised Periods I and II from January 2007 to May 2009, and from June 2009 [...] Read more.
Objective: We examined the association between non-alcoholic fatty liver disease (NAFLD) markers and fasting serum immunoreactive insulin (FIRI) and urinary albumin excretion (UAE). Subjects and methods: This study comprised Periods I and II from January 2007 to May 2009, and from June 2009 to December 2011, respectively. After excluding people with ethanol intake ≥210 g/week in men and ≥140 g/week in women, 961 people (613 men, 348 women; mean age: 44 years) were included. We evaluated the fatty liver using ultrasonography score (FLUS) and measured liver enzymes. Results: The mean observation period was 25 ± 9 months. We stratified people into two groups by fasting plasma glucose (FPG) in Period I. The cutoff point between the lower FPG and higher FPG was 100 mg/dL. In regression analysis, serum alanine aminotransferase (ALT) (p < 0.001), FLUS (p < 0.001) and γ-glutamyl transpeptidase (GGTP) (p = 0.022) in Period I were independently associated with FIRI in Period II, whereas in all participants FPG was not. ALT (p < 0.001) and GGTP (p = 0.001) were also independently associated with UAE in people with FPG < 100 mg/dL in Period II. Conclusions: Some NAFLD markers were associated with FIRI and UAE independently of fasting plasma glucose. Full article
(This article belongs to the Special Issue Should Physicians Consider NAFLD a Primary or Secondary Disease?)
Article
Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease
J. Clin. Med. 2020, 9(2), 314; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9020314 - 22 Jan 2020
Cited by 1 | Viewed by 1036
Abstract
Nonalcoholic liver disease (NAFLD) is manifested with a wide spectrum of clinical symptoms and is closely associated with the metabolic syndrome, inflammation, and mitochondrial dysfunction. Although the mechanism of mitochondrial dysfunction in NAFLD is still not fully elucidated, multiple studies have demonstrated evidence [...] Read more.
Nonalcoholic liver disease (NAFLD) is manifested with a wide spectrum of clinical symptoms and is closely associated with the metabolic syndrome, inflammation, and mitochondrial dysfunction. Although the mechanism of mitochondrial dysfunction in NAFLD is still not fully elucidated, multiple studies have demonstrated evidence of molecular, biochemical, and biophysical mitochondrial abnormalities in NAFLD. Given the association between NAFLD and mitochondrial dysfunction, the aim of this study is to analyze circulating levels of Krebs cycle intermediates in a cohort of NAFLD-affected individuals and matching healthy controls and to correlate our findings with the liver function metrics. Standard serum biochemistry and Krebs cycle intermediates were analyzed in NAFLD (n = 22) and matched control (n = 67) cohorts. Circulating levels of isocitrate and citrate were significantly (p < 0.05) elevated in the NAFLD cohort of patients. The area under the curve (AUROC) for these two metabolites exhibited a moderate clinical utility. Correlations between plasma Krebs cycle intermediates and standard clinical plasma metrics were explored by Pearson’s correlation coefficient. The data obtained for plasma Krebs cycle intermediates suggest pathophysiological insights that link mitochondrial dysfunction with NAFLD. Our findings reveal that plasma isocitrate and citrate can discriminate between normal and NAFLD cohorts and can be utilized as noninvasive markers of mitochondrial dysfunction in NAFLD. Future studies with large populations at different NAFLD stages are warranted. Full article
(This article belongs to the Special Issue Should Physicians Consider NAFLD a Primary or Secondary Disease?)
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Article
Randomised Clinical Trial: Calorie Restriction Regimen with Tomato Juice Supplementation Ameliorates Oxidative Stress and Preserves a Proper Immune Surveillance Modulating Mitochondrial Bioenergetics of T-Lymphocytes in Obese Children Affected by Non-Alcoholic Fatty Liver Disease (NAFLD)
J. Clin. Med. 2020, 9(1), 141; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9010141 - 04 Jan 2020
Cited by 9 | Viewed by 1569
Abstract
Fatty liver disease is a serious complication of childhood obesity. Calorie-restricted regimen (RCR) is one of the effective therapy for this condition. Aim of the study was to evaluate the effect of lycopene-rich tomato sauce with oregano and basil extracts in obese children [...] Read more.
Fatty liver disease is a serious complication of childhood obesity. Calorie-restricted regimen (RCR) is one of the effective therapy for this condition. Aim of the study was to evaluate the effect of lycopene-rich tomato sauce with oregano and basil extracts in obese children with fatty liver on RCR. 61 obese children with fatty liver were enrolled, 52 completed the study. A randomized cross over clinical trial was performed. Participants were assigned to RCR alone or with a supplement of lycopene-rich tomato juice for 60 days; subsequently, the groups were switched to the alternative regimen for the next 60 days. Reduction in BMI, HOMA-IR, cholesterol, triglycerides, liver size, and steatosis was more profound in tomato-supplemented group. Leptin decreased in both groups whereas adiponectin raised only after tomato supplementation. RCR is associated with the impaired engagement of T-cells glycolysis and proliferation, tomato-supplementation resulted in glycolytic metabolic activation of T-cells. Tomato juice ameliorates glucose and lipid metabolism in obese children, improve oxidative and inflammatory state and modulates the mitochondrial metabolism of T-cells contributing to a maintenance of a proper immune surveillance in children, impaired by RCR. The addition of tomato to RCR could be considered a protective and preventive support to obese child. Full article
(This article belongs to the Special Issue Should Physicians Consider NAFLD a Primary or Secondary Disease?)
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Review

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Review
Renaming NAFLD to MAFLD: Could the LDE System Assist in This Transition?
J. Clin. Med. 2021, 10(3), 492; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10030492 - 31 Jan 2021
Cited by 4 | Viewed by 909
Abstract
Our understanding of fatty liver syndromes and their relationship with the metabolic syndrome has improved over recent decades and, paralleling this, we are now at the dawn of the NAFLD (nonalcoholic fatty liver disease) to MAFLD (metabolic-associated fatty liver disease) transition. The pitfalls [...] Read more.
Our understanding of fatty liver syndromes and their relationship with the metabolic syndrome has improved over recent decades and, paralleling this, we are now at the dawn of the NAFLD (nonalcoholic fatty liver disease) to MAFLD (metabolic-associated fatty liver disease) transition. The pitfalls of NAFLD diagnosis, together with disappointing results in therapeutic trials, and the inconsistencies and risks inherent in a “negative” definition (such as “nonalcoholic”) as opposed to a “positive” one (i.e., “metabolic”) are predicted to facilitate the proposed renaming of NAFLD to MAFLD. However, a premature change of terminology would not necessarily address major unmet needs in this area, and may even become counterproductive. As an aid to selecting more homogeneous cohorts of patients, I propose the LDE (Liver, Determinants, Extra-hepatic) classification system which, in principle, may help to assess the natural course of disease as well as the efficacy of novel drugs in patients with NAFLD/MAFLD. Full article
(This article belongs to the Special Issue Should Physicians Consider NAFLD a Primary or Secondary Disease?)
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Review
Phytocannabinoids—A Green Approach toward Non-Alcoholic Fatty Liver Disease Treatment
J. Clin. Med. 2021, 10(3), 393; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10030393 - 20 Jan 2021
Cited by 1 | Viewed by 1011
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in adults in developed countries, with a global prevalence as high as one billion. The pathogenesis of NAFLD is a multifactorial and multi-step process. Nowadays, a growing body of research suggests [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in adults in developed countries, with a global prevalence as high as one billion. The pathogenesis of NAFLD is a multifactorial and multi-step process. Nowadays, a growing body of research suggests the considerable role of the endocannabinoid system (ECS) as a complex cell-signaling system in NAFLD development. Although increased endocannabinoid tone in the liver highly contributes to NAFLD development, the complex effects and impacts of plant-derived cannabinoids in the aspect of NAFLD pathophysiology are yet not fully understood, and effective medications are still in demand. In our review, we present the latest reports describing the role of ECS in NAFLD, focusing primarily on two types of cannabinoid receptors. Moreover, we sum up the recent literature on the clinical use of natural cannabinoids in NAFLD treatment. This review is useful for understanding the importance of ECS in NAFLD development, and it also provides the basis for more extensive clinical phytocannabinoids testing in patients suffering from NAFLD. Full article
(This article belongs to the Special Issue Should Physicians Consider NAFLD a Primary or Secondary Disease?)
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Review
Sexual Dimorphism of NAFLD in Adults. Focus on Clinical Aspects and Implications for Practice and Translational Research
J. Clin. Med. 2020, 9(5), 1278; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9051278 - 28 Apr 2020
Cited by 29 | Viewed by 1594
Abstract
Nonalcoholic fatty liver disease (NAFLD) embraces the clinico-pathological consequences of hepatic lipotoxicity and is a major public health problem globally. Sexual dimorphism is a definite feature of most human diseases but, under this aspect, NAFLD lags behind other medical fields. Here, we aim [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) embraces the clinico-pathological consequences of hepatic lipotoxicity and is a major public health problem globally. Sexual dimorphism is a definite feature of most human diseases but, under this aspect, NAFLD lags behind other medical fields. Here, we aim at summarizing and critically discussing the most prominent sex differences and gaps in NAFLD in humans, with emphasis on those aspects which are relevant for clinical practice and translational research. Sexual dimorphism of NAFLD is covered with references to the following areas: disease prevalence and risk factors, pathophysiology, comorbidities, natural course and complications. Finally, we also discuss selected gender differences and whether sex-specific lifestyle changes should be adopted to contrast NAFLD in men and women. Full article
(This article belongs to the Special Issue Should Physicians Consider NAFLD a Primary or Secondary Disease?)
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Review
Nonalcoholic Fatty Liver Disease: A Challenge from Mechanisms to Therapy
J. Clin. Med. 2020, 9(1), 15; https://doi.org/10.3390/jcm9010015 - 19 Dec 2019
Cited by 49 | Viewed by 2381
Abstract
Focusing on previously published mechanisms of non-alcoholic fatty liver disease (NAFLD), their uncertainty does not always permit a clear elucidation of the grassroot alterations that are at the basis of the wide-spread illness, and thus curing it is still a challenge. There is [...] Read more.
Focusing on previously published mechanisms of non-alcoholic fatty liver disease (NAFLD), their uncertainty does not always permit a clear elucidation of the grassroot alterations that are at the basis of the wide-spread illness, and thus curing it is still a challenge. There is somehow exceptional progress, but many controversies persist in NAFLD research and clinical investigation. It is likely that hidden mechanisms will be brought to light in the near future. Hereby, the authors present, with some criticism, classical mechanisms that stand at the basis of NAFLD, and consider contextually different emerging processes. Without ascertaining these complex interactions, investigators have a long way left ahead before finding an effective therapy for NAFLD beyond diet and exercise. Full article
(This article belongs to the Special Issue Should Physicians Consider NAFLD a Primary or Secondary Disease?)
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