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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 (29 February 2020) | Viewed by 32025

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Prof. Dr. Stefano Fiorucci

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Gastroenterology Section, Department of Surgical and Biomedical Sciences, School of Medicine, University of Perugia, 06132 Perugia, Italy
Interests: innate immunity; intestinal immunity; liver immunity; nuclear receptors; mucosal immunity; intestinal microbiota
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Dear Colleagues,

Nonalcoholic fatty liver disease (NAFLD) is a common liver disorder with a high prevalence (20–30%) in Western as well as many Eastern countries, thus representing a rapidly growing health problem worldwide. NAFLD includes a spectrum of disorders ranging from non-alcoholic fatty liver (NAFL), a reversible condition caused by a lipid deposition in the hepatocytes, to non-alcoholic steatohepatitis (NASH), characterized by hepatocytes ballooning and inflammatory cell infiltration. Despite its lower prevalence, ranging from 1.5 to 6.5%, NASH is a progressive liver disease associated with an increased significant risk of developing parenchymal fibrosis, hepatic cirrhosis, and hepatocellular carcinoma. Furthermore, both diseases involve an increased risk for developing cardiovascular complications, including coronary heart disease and stroke. NASH could be considered the hepatic manifestation of metabolic syndrome. The development of NASH is associated with the presence of risk factors, such as weight gain, diabetes, hypertension, menopause, and genetic conditions. Over time, obesity is considered a primary cause of NAFLD and NASH. The accumulation of lipid species, in particular fatty acids, in hepatocytes exerts lipotoxic effects that cause progressive parenchymal cell loss, inflammation, and fibrosis in NASH. However, the pathogenesis of NASH is multifactorial, involving environmental factors, in particular excessive caloric intake associated with a genetic predisposition, but requires second hits, represented by insulin resistance and visceral adipose tissue inflammation, which are thought to be central to the pathogenesis of NASH. To date, there are several available rodent models of NAFLD and NASH, whose relevance to the human NASH is imperfect because they have shown substantial heterogeneity of gene and pathway regulation in comparison to human NASH. However, steatohepatitis induced by long-term administration of a high-fat diet (HFD) and fructose leading to steatosis, inflammation, and fibrosis shows a better correlation to human NAFLD and NASH, confirming the importance of preclinical models. Several agents are currently under development for the treatment of NASH in 2019, but there are no approved drugs to treat this condition. In summary, there is an urgent need to develop novel approaches to treat NASH patients.

Prof. Dr. Stefano Fiorucci
Guest Editor

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Keywords

Bile acids
Liver lipids
Cholesterol
Steatohepatatis
Liver fibrosis
Animal models
Clinical trials
Metabolic syndrome
Drug development
Nuclear receptors
FXR
PPARs
Cholesterol biosynthesis
Diabetes
Obesity
Vascular complications
Liver cirrhosis
Hepatocarcinoma
Bariatric surgery

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Published Papers (7 papers)

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23 pages, 7547 KiB

Open AccessArticle

Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD

by Sarthak Sahoo, Divyoj Singh, Priyanka Chakraborty and Mohit Kumar Jolly

J. Clin. Med. 2020, 9(3), 870; https://doi.org/10.3390/jcm9030870 - 22 Mar 2020

Cited by 15 | Viewed by 5908

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in adults and children. It is characterized by excessive accumulation of lipids in the hepatocytes of patients without any excess alcohol intake. With a global presence of 24% and limited therapeutic options, the disease burden of NAFLD is increasing. Thus, it becomes imperative to attempt to understand the dynamics of disease progression at a systems-level. Here, we decoded the emergent dynamics of underlying gene regulatory networks that were identified to drive the initiation and the progression of NAFLD. We developed a mathematical model to elucidate the dynamics of the HNF4α-PPARγ gene regulatory network. Our simulations reveal that this network can enable multiple co-existing phenotypes under certain biological conditions: an adipocyte, a hepatocyte, and a “hybrid” adipocyte-like state of the hepatocyte. These phenotypes may also switch among each other, thus enabling phenotypic plasticity and consequently leading to simultaneous deregulation of the levels of molecules that maintain a hepatic identity and/or facilitate a partial or complete acquisition of adipocytic traits. These predicted trends are supported by the analysis of clinical data, further substantiating the putative role of phenotypic plasticity in driving NAFLD. Our results unravel how the emergent dynamics of underlying regulatory networks can promote phenotypic plasticity, thereby propelling the clinically observed changes in gene expression often associated with NAFLD. Full article

(This article belongs to the Special Issue Non-Alcoholic Steatohepatitis (NASH))

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10 pages, 248 KiB

Open AccessArticle

The Association between SOCS1−1656G>A Polymorphism, Insulin Resistance and Obesity in Nonalcoholic Fatty Liver Disease (NAFLD) Patients

by Agnieszka Kempinska-Podhorodecka, Ewa Wunsch, Piotr Milkiewicz, Ewa Stachowska and Malgorzata Milkiewicz

J. Clin. Med. 2019, 8(11), 1912; https://doi.org/10.3390/jcm8111912 - 8 Nov 2019

Cited by 8 | Viewed by 2335

Abstract

Suppressor of cytokine signaling (SOCS) proteins prevent uncontrolled cytokine signaling and appear to play a role in the pathological processes behind obesity and insulin resistance. The polymorphism of the SOCS1 gene (rs243330, −1656G>A) is associated with obesity and glucose sensitivity. To estimate the effect of this SOCS1 gene polymorphism on nonalcoholic fatty liver disease (NAFLD) susceptibility, we performed a study on 138 patients with ultrasound-confirmed NAFLD and 1000 healthy blood donors. The relationship between the SOCS1−1656G>A polymorphism and serum biochemical parameters in NAFLD was additionally investigated. The SOCS1 variant was genotyped using a dedicated TaqMan assay. The frequency of rs243330 polymorphism did not differ between patients and controls. However, in a cohort of obese individuals (BMI ≥ 30 kg/m²) the occurrence of the G allele of the SOCS1−1656G>A polymorphism was strongly associated with NAFLD (odds ratio (OR) 1.6; 95% CI,1.1–2.5; p = 0.009), and carriers of the AA genotype have lower risk of developing NAFLD (OR 0.4; 95% CI, 0.2–0.7; p = 0.004). Overweight NAFLD patients who were carriers of GG genotypes had significantly lower levels of homeostasis model assessment of insulin resistance (HOMA-IR) values (p = 0.03 vs. AA), and the obese GG homozygotes had lower serum concertation of triglyceride (GG vs. AA; p = 0.02). Serum liver enzyme activities were not modified by the presence of SOCS1 risk variants. In conclusion, the observed phenotype of overweight NAFLD patients with non-elevated levels of TG and HOMA-IR, which is associated with genetic variants of SOCS1, provides a rationale for further research on the pathophysiology of fatty liver disease. Full article

(This article belongs to the Special Issue Non-Alcoholic Steatohepatitis (NASH))

17 pages, 838 KiB

Open AccessArticle

Is There a Link between Basal Metabolic Rate, Spleen Volume and Hepatic Growth Factor Levels in Patients with Obesity-Related NAFLD?

by Giovanni Tarantino, Vincenzo Citro, Paolo Conforti, Clara Balsano and Domenico Capone

J. Clin. Med. 2019, 8(10), 1510; https://doi.org/10.3390/jcm8101510 - 20 Sep 2019

Cited by 11 | Viewed by 3652

Abstract

Background: Recent pieces of research point to a link between basal metabolic rate (BMR) and non-alcoholic fatty liver disease (NAFLD) or hepatic steatosis (HS). The spleen in obese patients is associated with the cardiovascular system. Enlargement of the spleen is suggestive of nonalcoholic steatohepatitis (NASH). Patients with NASH present an increase in growth factor (HGF) as well as those with advanced heart failure. Interleukin-16 and interleukin-12p40 levels were found to correlate significantly with BMI, and waist circumference. Aim: We tried to find a relationship between BMR, spleen length and HGF. Methods: We analysed retrospective data from 80 obese patients with NAFLD. We evaluated indices of indirect calorimetry by the bioimpendance analysis; carotid intima-media thickness (IMT), spleen length (SLD) and HS by ultrasonography; serum HGF, IL-16, IL-12p40 and IL-6 concentrations by a magnetic bead-based multiplex immunoassays and the severity of NAFLD by BARD score > 2. Results: HGF levels of the obese were higher than those of controls, p < 0.001. At linear regression, BMR was foreseen by spleen length (p < 0.001), which was predicted by HGF (p = 0.04). BMR was predicted by IL-16 (p = 0.005), which predicted HGF, p = 0.034. Only fat mass, among other factors, predicted early atherosclerosis, p = 0.017; IL-12p40 did not predict IMT, HGF and BMR (p = 0.57, 0.09 and 0.59, respectively). The BARD score > 2 was negatively predicted by BMR and FFM (p =0.032 and 0.031, respectively), at the logistic regression. Interesting findings at the extended regression (mediation effect) were: IL-16 was likely causal in predicting BMR by HGF levels; HGF was influential in predicting BMR by SLD level. HS was predicted by SLD in males (p = 0.014), of advanced age (p < 0.001) and by BMR (p < 0.001). IL-6 concentrations, but not BMR were influential in the prediction of HS by SLD. Conclusion: These data reinforce the concept that the immune system is a sensor of the metabolic state, showing a link between HGF levels and BMR, which is mediated by IL-16 (cytokine inducing a cascade of inflammatory factors), and ascertaining the influential effect of the spleen, as main immune organ. Full article

(This article belongs to the Special Issue Non-Alcoholic Steatohepatitis (NASH))

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13 pages, 420 KiB

Open AccessArticle

Serum Vitamin E Levels of Adults with Nonalcoholic Fatty Liver Disease: An Inverse Relationship with All-Cause Mortality in Non-Diabetic but Not in Pre-Diabetic or Diabetic Subjects

by Peiling Tsou and Chang-Jiun Wu

J. Clin. Med. 2019, 8(7), 1057; https://doi.org/10.3390/jcm8071057 - 19 Jul 2019

Cited by 10 | Viewed by 3640

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a growing health threat worldwide. Vitamin E supplementation is recommended for nonalcoholic steatohepatitis (NASH) patients, but only for non-diabetic subjects. We aimed to investigate whether serum vitamin E levels differently impact long-term prognosis in diabetic versus non-diabetic NAFLD individuals. A total of 2404 ultrasonographically defined NAFLD individuals from National Health and Nutrition Examination Survey (NHANES) III were stratified by their glycemic statuses into diabetic (N = 662), pre-diabetic (N = 836) and non-diabetic (N = 906), and the relationship between serum vitamin E levels and all-cause mortality was analyzed. The serum vitamin E concentrations were 31.1 ± 14.1, 26.7 ± 9.6, and 24.7 ± 9.8 µmol/L and vitamin E: total cholesterol ratios were 5.16 ± 1.70, 4.81 ± 1.46, and 4.80 ± 1.34 µmol/mmol in in diabetic, pre-diabetic, and non-diabetic groups, respectively. Of 2404 NAFLD subjects, 2403 have mortality information and 152 non-diabetic, 244 pre-diabetic, and 342 diabetic participants died over a median follow-up period of 18.8 years. Both serum vitamin E levels and vitamin E: total cholesterol ratios were negatively associated with all-cause mortality after adjusting for possible confounders in non-diabetic subjects (HR = 0.483, and 0.451, respectively, p < 0.005), but not in either diabetic or pre-diabetic subjects. In NAFLD individuals, both serum vitamin E and lipid-corrected vitamin E were (1) higher in the diabetic group; and (2) negatively associated with all-cause mortality only in the non-diabetic group. Further investigations are warranted to elucidate the underlying mechanism of this inverse association of serum vitamin E concentration with all-cause mortality in non-diabetic but not pre-diabetic or diabetic subjects. Full article

(This article belongs to the Special Issue Non-Alcoholic Steatohepatitis (NASH))

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9 pages, 247 KiB

Open AccessArticle

Effect of Short Term Intensive Lifestyle Intervention on Hepatic Steatosis Indexes in Adults with Obesity and/or Type 2 Diabetes

by Elisa Reginato, Roberto Pippi, Cristina Aiello, Emilia Sbroma Tomaro, Claudia Ranucci, Livia Buratta, Vittorio Bini, Giulio Marchesini, Pierpaolo De Feo and Carmine Fanelli

J. Clin. Med. 2019, 8(6), 851; https://doi.org/10.3390/jcm8060851 - 14 Jun 2019

Cited by 21 | Viewed by 3459

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) has an estimated prevalence of 20–30% in the general population and even higher in individuals with metabolic risk factors. The aim of this study was to evaluate the effect of a lifestyle intervention program on surrogate markers of hepatic steatosis in obesity and/or type 2 diabetes patients, enrolled in the C.U.R.I.A.Mo. (Centro Universitario di Ricerca Interdipartimentale Attività Motoria) trial. Methods: 102 subjects (56 females and 46 males, aged between 23 and 78) with type 2 diabetes, obesity or a BMI of at least 25 kg/m² with comorbidities, participated in the intensive phase of a multidisciplinary lifestyle intervention program at the Healthy Lifestyle Institute of the University of Perugia (C.U.R.I.A.Mo.). Six indices related to NAFLD (Visceral Adiposity Index, Fatty Liver index, Non-Alcoholic Fatty Liver Disease liver fat score and liver fat equation, hepatic steatosis index and TyG index) were calculated before and after a three-month multidisciplinary lifestyle intervention. Results: The intervention improved the anthropometric and clinical parameters in the total population, the obese and/or diabetics. Data showed a significant weight loss, a reduced waist circumference, triglycerides, and an improvement in Mediterranean diet adherence. Hepatic steatosis indices were significantly reduced in the total population and in different subgroups (males, females, obesity and diabetes). Full article

(This article belongs to the Special Issue Non-Alcoholic Steatohepatitis (NASH))

13 pages, 1763 KiB

Open AccessArticle

Lysosomal Acid Lipase as a Molecular Target of the Very Low Carbohydrate Ketogenic Diet in Morbidly Obese Patients: The Potential Effects on Liver Steatosis and Cardiovascular Risk Factors

by Stefano Ministrini, Lucia Calzini, Elisa Nulli Migliola, Maria Anastasia Ricci, Anna Rita Roscini, Donatella Siepi, Giulia Tozzi, Giulia Daviddi, Eva-Edvige Martorelli, Maria Teresa Paganelli and Graziana Lupattelli

J. Clin. Med. 2019, 8(5), 621; https://doi.org/10.3390/jcm8050621 - 7 May 2019

Cited by 26 | Viewed by 6294

Abstract

A very low carbohydrate ketogenic diet (VLCKD) is an emerging technique to induce a significant, well-tolerated, and rapid loss of body weight in morbidly obese patients. The low activity of lysosomal acid lipase (LAL) could be involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), which is a common feature in morbidly obese patients. Fifty-two obese patients suitable for a bariatric surgery intervention underwent a 25-day-long VLCKD. The biochemical markers of glucose and lipid metabolism, and flow-mediated dilation (FMD) of the brachial artery were measured before and after VLCKD. LAL activity was measured using the dried blood spot technique in 20 obese patients and in a control group of 20 healthy, normal-weight subjects. After VLCKD, we observed a significant reduction in body mass index, fasting glucose, insulinemia, and lipid profile parameters. No significant variation in FMD was observed. The number of patients with severe liver steatosis significantly decreased. LAL activity significantly increased, although the levels were not significantly different as compared to the control group. In conclusion, VLCKD induces the activity of LAL in morbidly obese subjects and reduces the secretion of all circulating lipoproteins. These effects could be attributed to the peculiar composition of the diet, which is particularly poor in carbohydrates and relatively rich in proteins. Full article

(This article belongs to the Special Issue Non-Alcoholic Steatohepatitis (NASH))

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24 pages, 1014 KiB

Open AccessReview

A Systematic Review of NAFLD-Associated Extrahepatic Disorders in Youths

by Lucia Pacifico, Francesco Massimo Perla, Mario Roggini, Gianmarco Andreoli, Miriam D’Avanzo and Claudio Chiesa

J. Clin. Med. 2019, 8(6), 868; https://doi.org/10.3390/jcm8060868 - 17 Jun 2019

Cited by 23 | Viewed by 5725

Abstract

Background: There is growing evidence that non-alcoholic fatty liver disease (NAFLD) is a disease affecting not only the liver but also extrahepatic organs. Aim: To investigate whether in youths NAFLD is associated with extrahepatic complications such as subclinical atherosclerosis, cardiac abnormalities, hypertension, type 2 diabetes, decreased bone mineral density, renal dysfunction, obstructive sleep apnea, and polycystic ovary syndrome. Methods: We systematically reviewed PubMed; Scopus; Embase; and the Cochrane Library databases up to 28 February 2019 and assessed the quality of studies using the Newcastle-Ottawa Scale. Results: Thirty-five articles were selected for this systematic review: fifteen (4627 participants) evaluated the association of NAFLD with subclinical atherosclerosis; four (969 participants) with cardiac abnormalities; two (550 participants) with hypertension; four (1328 participants) with diabetes; six (523 participants) with low bone mineral density; two (865 participants) with renal dysfunction; one with obstructive sleep apnea; and one with polycystic ovary syndrome. Most studies found that youths with NAFLD have increased features of subclinical atherosclerosis; as well as of cardiac alterations. Limited data were available to endorse a solid estimate of the prevalence of diabetes; low mineral density and renal dysfunction in the pediatric NAFLD population. Conclusion: NAFLD-related intermediate CVD outcomes can occur and be detected early in young populations. Full article

(This article belongs to the Special Issue Non-Alcoholic Steatohepatitis (NASH))

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