Beyond the Paradigm of Weight Loss in Non-Alcoholic Fatty Liver Disease: From Pathophysiology to Novel Dietary Approaches

Current treatment recommendations for non-alcoholic fatty liver disease (NAFLD) rely heavily on lifestyle interventions. The Mediterranean diet and physical activity, aiming at weight loss, have shown good results in achieving an improvement of this liver disease. However, concerns related to compliance and food accessibility limit the feasibility of this approach, and data on the long-term effects on liver-related outcomes are lacking. Insulin resistance is a central aspect in the pathophysiology of NAFLD; therefore, interventions aiming at the improvement of insulin sensitivity may be preferable. In this literature review, we provide a comprehensive summary of the available evidence on nutritional approaches in the management of NAFLD, involving low-calorie diets, isocaloric diets, and the novel schemes of intermittent fasting. In addition, we explore the harmful role of single nutrients on liver-specific key metabolic pathways, the role of gene susceptibility and microbiota, and behavioral aspects that may impact liver disease and are often underreported in clinical setting. At present, the high variability in terms of study populations and liver-specific outcomes within nutritional studies limits the generalizability of the results and highlights the urgent need of a tailored and standardized approach, as seen in regulatory trials in Non-Alcoholic Steatohepatitis (NASH).

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DNA methylation signatures in non-alcoholic fatty liver disease reveal disease-specific signatures and molecular remodelling drivers after weight loss in non-alcoholic fatty liver disease

Zeitschrift für Gastroenterologie ◽

10.1055/s-0032-1331961 ◽

2013 ◽

Vol 51 (01) ◽

Author(s):

M Ahrens ◽

O Ammerpohl ◽

W von Schönfels ◽

T Itzel ◽

A Teufel ◽

...

Keyword(s):

Dna Methylation ◽

Weight Loss ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease ◽

Disease Specific

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The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease

Journal of Clinical Medicine ◽

10.3390/jcm10051081 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1081

Author(s):

Mikkel Parsberg Werge ◽

Adrian McCann ◽

Elisabeth Douglas Galsgaard ◽

Dorte Holst ◽

Anne Bugge ◽

...

Keyword(s):

Liver Disease ◽

Animal Models ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Precise Control ◽

Transsulfuration Pathway ◽

Global Population ◽

Alcoholic Fatty Liver Disease

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.

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Patient disease knowledge, attitudes and behaviours related to non-alcoholic fatty liver disease: a qualitative study

BMJ Open Gastroenterology ◽

10.1136/bmjgast-2021-000634 ◽

2021 ◽

Vol 8 (1) ◽

pp. e000634

Author(s):

Monica A Tincopa ◽

Jane Wong ◽

Michael Fetters ◽

Anna S Lok

Keyword(s):

Social Support ◽

Weight Loss ◽

Liver Disease ◽

Fatty Liver ◽

Health Behaviour ◽

Fatty Liver Disease ◽

Primary Therapy ◽

Alcoholic Fatty Liver ◽

Medical Comorbidities ◽

Alcoholic Fatty Liver Disease

ObjectiveDespite clear evidence that weight loss via nutritional and physical activity changes improves histological outcomes in non-alcoholic fatty liver disease (NAFLD), many patients struggle to implement and maintain these health behaviour changes. The aim of this study was to characterise disease knowledge, attitudes and behaviours among persons with NAFLD and to identify the factors driving these health behaviours and perceptions.DesignWe conducted semistructured interviews among patients with NAFLD. We used purposeful sampling to enroll equivalent percentages based on age and sex, and enrolled approximately one-third of patients with cirrhosis to capture those perspectives. Interviews were conducted until thematic saturation was achieved. Transcripts were coded using NVivo software to identify themes and subthemes.ResultsA total of 29 patient interviews were completed. Ambiguity about the diagnosis and aetiology of their liver disease was a key theme, though the vast majority of patients were aware that weight loss via nutrition and exercise was the primary therapy. Most patients were asymptomatic, diagnosed incidentally, and reported low level of concern regarding their diagnosis. The primary barriers and facilitators to health behaviour change were the presence of social support, competing medical comorbidities and low motivation to change behaviours.ConclusionsAlthough patients are aware that lifestyle interventions are the primary therapy for NAFLD, there is a gap in knowledge about the condition. The presence of social support and competing medical comorbidities were the most consistent facilitators and barriers to lifestyle change. Tailoring treatment recommendations to provide relevant disease education, specific nutrition and exercise regimens, and personalised approaches based on specific individual barriers and facilitators will likely aid in uptake and maintenance of first-line therapy for NAFLD.

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The Role of Oxidative Stress in NAFLD–NASH–HCC Transition—Focus on NADPH Oxidases

Biomedicines ◽

10.3390/biomedicines9060687 ◽

2021 ◽

Vol 9 (6) ◽

pp. 687

Author(s):

Daniela Gabbia ◽

Luana Cannella ◽

Sara De De Martin

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Current Knowledge ◽

Mechanisms Of Action ◽

Nadph Oxidases ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development.

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Role of illness perception and self-efficacy in lifestyle modification among non-alcoholic fatty liver disease patients

World Journal of Gastroenterology ◽

10.3748/wjg.v23.i10.1881 ◽

2017 ◽

Vol 23 (10) ◽

pp. 1881 ◽

Cited By ~ 19

Author(s):

Shira Zelber-Sagi ◽

Shiran Bord ◽

Gali Dror-Lavi ◽

Matthew Lee Smith ◽

Samuel D Towne Jr ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Self Efficacy ◽

Fatty Liver Disease ◽

Lifestyle Modification ◽

Illness Perception ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

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A 12-week multi-component dietary intervention improves markers of non-alcoholic fatty liver disease in Irish patients in tertiary care

Proceedings of The Nutrition Society ◽

10.1017/s002966512000453x ◽

2020 ◽

Vol 79 (OCE2) ◽

Author(s):

Deirdre Ní Fhloinn ◽

Ciara Wright ◽

Sara Naimimohasses ◽

Stephen Finn ◽

Suzanne Norris ◽

...

Keyword(s):

Weight Loss ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Dietary Intervention ◽

Tertiary Care ◽

Intervention Group ◽

Post Intervention ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

AbstractNon-alcoholic fatty liver disease (NAFLD) is a significant public health concern closely linked to obesity, affecting an estimated 25% of adults in Europe. Understudied in Ireland, the aim of this research was to examine the effects of a 12-week multi-component dietary intervention on weight loss and markers of liver injury in Irish NAFLD patients in tertiary care. Biopsy confirmed NAFLD patients (n = 27) were recruited from St James’ Hospital in Dublin, Ireland. Consenting participants underwent a 12-week moderate-intensity intervention incorporating weekly group nutritional education, behavioural change and group support, as well as individualised advice and weigh-ins from a trained nutritionist. Control group participants were given routine clinical care. All participants were clinically reviewed before, immediately after, and 3 months post intervention. Individuals (n = 12) with histological evidence of steatohepatitis underwent a repeat liver biopsy on completion of the intervention. Detailed dietary assessment was performed using both a 4-day diet diary (4DDD) and a novel, recently validated, short food frequency questionnaire (SFFQ) designed specifically to assess habitual intakes of food items related to NAFLD. Nutrient intakes were analysed using myFood24TM dietary analysis software, and the Mediterranean diet quality score (MDQS) was used to assess the overall change in dietary patterns. Of the 15 participants who completed the intervention, 80% (n = 12) achieved a weight loss exceeding 5%, with 47% (n = 7) achieving > 7%. There were significant improvements from baseline to week 12 in the intervention group for the majority of clinical parameters including HbA1c (p = 0.0054), liver enzymes (ALT, p = 0.0108; GGT, p = 0.0001) and transient elastography (kPA, p = 0.0308; CAP, p = 0.0081). However, these results failed to maintain significance when analysed compared to controls. The overall dietary pattern was significantly improved after 12 weeks as assessed by the MDQS (p = 0.03), with no apparent compromise in micronutrient intake despite the energy reduction. Reductions in energy, saturated fat, carbohydrate and sugar intakes at 12 weeks, were maintained at three months follow up. Analysis of pre- and post-intervention liver biopsies in the intervention group demonstrated a clinically significant improvement in NAS score (p = 0.0273), attributable to reductions in hepatic steatosis (p = 0.0078). A significant correlation was observed between improvement in liver histology and change in sugar intake (r = 0.7534, p = 0.0093). Although results were somewhat limited by small sample size, nutritional education achieved beneficial dietary changes that persisted after the intervention ceased. Notably, achieving reductions in sugar intakes may be particularly beneficial in reducing the severity of hepatic steatosis in Irish adults with NAFLD.

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A Narrative Review on the Role of AMPK on De Novo Lipogenesis in Non-Alcoholic Fatty Liver Disease: Evidence from Human Studies

Cells ◽

10.3390/cells10071822 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1822

Author(s):

Christian von Loeffelholz ◽

Sina M. Coldewey ◽

Andreas L. Birkenfeld

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Mammalian Cells ◽

De Novo ◽

Adenosine Monophosphate ◽

De Novo Lipogenesis ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

5′AMP-activated protein kinase (AMPK) is known as metabolic sensor in mammalian cells that becomes activated by an increasing adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio. The heterotrimeric AMPK protein comprises three subunits, each of which has multiple phosphorylation sites, playing an important role in the regulation of essential molecular pathways. By phosphorylation of downstream proteins and modulation of gene transcription AMPK functions as a master switch of energy homeostasis in tissues with high metabolic turnover, such as the liver, skeletal muscle, and adipose tissue. Regulation of AMPK under conditions of chronic caloric oversupply emerged as substantial research target to get deeper insight into the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Evidence supporting the role of AMPK in NAFLD is mainly derived from preclinical cell culture and animal studies. Dysbalanced de novo lipogenesis has been identified as one of the key processes in NAFLD pathogenesis. Thus, the scope of this review is to provide an integrative overview of evidence, in particular from clinical studies and human samples, on the role of AMPK in the regulation of primarily de novo lipogenesis in human NAFLD.

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