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Cited by 136Liver Disease Diagnosis and TreatmentAlcohol Consumption and Health EffectsLiver physiology and pathology

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Non-alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease: Two Intertwined Entities

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Idalsoaga, Francisco, Kulkarni, Anand V., Mousa, Omar Y., Arrese, Marco, Arab, Juan Pablo·2020·Frontiers in Medicine
DOI 10.3389/fmed.2020.00448PMC PMC7468507
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Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, with a prevalence of 25-30%. Since its first description in 1980, NAFLD has been conceived as a different entity from alcohol-related fatty liver disease (ALD), despite that, both diseases have an overlap in the pathophysiology, share genetic-epigenetic factors, and frequently coexist. Both entities are characterized by a broad spectrum of histological features ranging from isolated steatosis to steatohepatitis and cirrhosis. Distinction between NAFLD and ALD is based on the amount of consumed alcohol, which has been arbitrarily established. In this context, a proposal of positive criteria for NAFLD diagnosis not considering exclusion of alcohol consumption as a prerequisite criterion for diagnosis had emerged, recognizing the possibility of a dual etiology of fatty liver in some individuals. The impact of moderate alcohol use on the severity of NAFLD is ill-defined. Some studies suggest protective effects in moderate doses, but current evidence shows that there is no safe threshold for alcohol consumption for NAFLD. In fact, given the synergistic effect between alcohol consumption, obesity, and metabolic dysfunction, it is likely that alcohol use serves as a significant risk factor for the progression of liver disease in NAFLD and metabolic syndrome. This also affects the incidence of hepatocellular carcinoma. In this review, we summarize the overlapping pathophysiology of NAFLD and ALD, the current data on alcohol consumption in patients with NAFLD, and the effects of metabolic dysfunction and overweight in ALD.

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Figure 1 Spectrum of fatty liver diseases. In non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease have been generally conceived as different entities, and despite that both conditions share an overlapping pathophysiology and frequently coexist in clinical practice, thresholds to diagnose NAFLD makes difficult to account for a dual etiology in a given patient. For that reason, a nomenclature change has been proposed [see (71) in the main text] considering that at the ends of the spectrum of fatty liver disease, there are patients with true ALD (now named alcohol-associated fatty liver disease, AAFLD) and some with true NAFLD with alcohol consumption near-zero (now named metabolic associated fatty liver disease, MAFLD) but that the vast majority of patients are between these two extremes. Thus, in clinical practice there will be patients with ALD that have metabolic cofactors (AAFLD with MetS) and patients with NAFLD that consume alcohol, which contributes to the disease process (MAFLD with alcohol component). In the middle, a large group of patients have both conditions (NAFLD and ALD) with some showing an equal contribution of alcohol and metabolic factors (proposedly named as both alcohol and metabolic associated fatty liver disease, BAFLD).
Figure 1 Spectrum of fatty liver diseases. In non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease have been generally conceived as different entities, and despite that both conditions share an overlapping pathophysiology and frequently coexist in clinical practice, thresholds to diagnose NAFLD makes difficult to account for a dual etiology in a given patient. For that reason, a nomenclature change has been proposed [see (71) in the main text] considering that at the ends of the spectrum of fatty liver disease, there are patients with true ALD (now named alcohol-associated fatty liver disease, AAFLD) and some with true NAFLD with alcohol consumption near-zero (now named metabolic associated fatty liver disease, MAFLD) but that the vast majority of patients are between these two extremes. Thus, in clinical practice there will be patients with ALD that have metabolic cofactors (AAFLD with MetS) and patients with NAFLD that consume alcohol, which contributes to the disease process (MAFLD with alcohol component). In the middle, a large group of patients have both conditions (NAFLD and ALD) with some showing an equal contribution of alcohol and metabolic factors (proposedly named as both alcohol and metabolic associated fatty liver disease, BAFLD).CC BY · PubMed Central
Figure 2 Proposed algorithm to approach patients with liver steatosis. A staggered algorithm to approach patients with liver steatosis is shown. This algorithm considers alcohol intake and metabolic cofactors (obesity, T2DM, and MetS) and classifies patients in AAFLD alcohol-associated fatty liver disease (true ALD) if hazardous alcohol intake is present, AAFLD with metabolic component (predominant ALD but with metabolic cofactors), MAFLD metabolic associated fatty liver disease (NAFLD with alcohol consumption near zero), MAFLD with alcohol component (NAFLD but with alcohol consumption contributing to the disease process), and finally BAFLD both alcohol and metabolic associated fatty liver disease (patients with both NAFLD and ALD equally contributing or no possible to determine which predominates). Criteria to diagnose MAFLD are suggested in (72) in the main text.
Figure 2 Proposed algorithm to approach patients with liver steatosis. A staggered algorithm to approach patients with liver steatosis is shown. This algorithm considers alcohol intake and metabolic cofactors (obesity, T2DM, and MetS) and classifies patients in AAFLD alcohol-associated fatty liver disease (true ALD) if hazardous alcohol intake is present, AAFLD with metabolic component (predominant ALD but with metabolic cofactors), MAFLD metabolic associated fatty liver disease (NAFLD with alcohol consumption near zero), MAFLD with alcohol component (NAFLD but with alcohol consumption contributing to the disease process), and finally BAFLD both alcohol and metabolic associated fatty liver disease (patients with both NAFLD and ALD equally contributing or no possible to determine which predominates). Criteria to diagnose MAFLD are suggested in (72) in the main text.CC BY · PubMed Central
Figure 3 NAFLD/ALD overlapping pathogenic processes. Free fatty acids (FFA) and ethanol have a myriad of effects on hepatocytes determining, among other phenomena, the occurrence of mitochondrial dysfunction, endoplasmic reticulum (ER) stress (resulting in impaired protein folding), and excessive production of ROS, which result in hepatocellular injury, activation of other cell death pathways, and inflammasome activation. Damaged hepatocytes release damage-associated molecular pattern (DAMP) molecules [e.g., high-mobility group box 1 (HMGB1)] that signal to Kupffer and hepatic stellate cells (HSC), fueling inflammation and fibrogenesis. Extracellular vesicle (EV) release from hepatocytes also contributes to both Kupffer cell and HSC activation. In non-alcoholic fatty liver disease (NAFLD), insulin resistance (IR) is a central phenomenon promoting adipose tissue lipolysis and an increased FFA flux to the liver. This FFA overflow surpasses the storage capacity of hepatocytes and determines the occurrence of lipotoxicity and activation of cell death pathways. Also, adipose tissue dysfunction is associated with a proinflammatory state with elevated levels of circulating cytokines [e.g., tumor necrosis factor-α (TNF-α) and interleukin (IL)-6] and with an imbalance in circulating levels of adipose tissue-derived adipokines (i.e., a decrease in adiponectin and an increase in leptin). This may increase IR and contribute to HSC activation. Of note, some nuclear receptors such as peroxisome proliferator-activated receptors (PPARs) and farnesoid X receptor (FXR), a bile acid receptor, may have anti-inflammatory and anti-steatotic effects, which are being exploited therapeutically. Both NAFLD and ALD (alcohol-related liver disease) are associated with intestinal dysbiosis and altered gut permeability, which results in the pass of bacterial products [e.g., pathogen-associated molecular patterns (PAMPs), lipopolysaccharides (LPS), and others] into portal circulation. In the liver, LPS and PAMPS may activate different Toll-like receptors (TLRs) as well as promote inflammasome assembly determining amplification of inflammatory responses. In ALD, proinflammatory cytokines released from macrophages may also activate cell death receptors and induce apoptosis.
Figure 3 NAFLD/ALD overlapping pathogenic processes. Free fatty acids (FFA) and ethanol have a myriad of effects on hepatocytes determining, among other phenomena, the occurrence of mitochondrial dysfunction, endoplasmic reticulum (ER) stress (resulting in impaired protein folding), and excessive production of ROS, which result in hepatocellular injury, activation of other cell death pathways, and inflammasome activation. Damaged hepatocytes release damage-associated molecular pattern (DAMP) molecules [e.g., high-mobility group box 1 (HMGB1)] that signal to Kupffer and hepatic stellate cells (HSC), fueling inflammation and fibrogenesis. Extracellular vesicle (EV) release from hepatocytes also contributes to both Kupffer cell and HSC activation. In non-alcoholic fatty liver disease (NAFLD), insulin resistance (IR) is a central phenomenon promoting adipose tissue lipolysis and an increased FFA flux to the liver. This FFA overflow surpasses the storage capacity of hepatocytes and determines the occurrence of lipotoxicity and activation of cell death pathways. Also, adipose tissue dysfunction is associated with a proinflammatory state with elevated levels of circulating cytokines [e.g., tumor necrosis factor-α (TNF-α) and interleukin (IL)-6] and with an imbalance in circulating levels of adipose tissue-derived adipokines (i.e., a decrease in adiponectin and an increase in leptin). This may increase IR and contribute to HSC activation. Of note, some nuclear receptors such as peroxisome proliferator-activated receptors (PPARs) and farnesoid X receptor (FXR), a bile acid receptor, may have anti-inflammatory and anti-steatotic effects, which are being exploited therapeutically. Both NAFLD and ALD (alcohol-related liver disease) are associated with intestinal dysbiosis and altered gut permeability, which results in the pass of bacterial products [e.g., pathogen-associated molecular patterns (PAMPs), lipopolysaccharides (LPS), and others] into portal circulation. In the liver, LPS and PAMPS may activate different Toll-like receptors (TLRs) as well as promote inflammasome assembly determining amplification of inflammatory responses. In ALD, proinflammatory cytokines released from macrophages may also activate cell death receptors and induce apoptosis.CC BY · PubMed Central

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Metadata

Authors
Idalsoaga, F., Kulkarni, A. V., Mousa, O. Y., Arrese, M., & Arab, J. P.
Affiliations
  • Pontificia Universidad Católica de Chile (CL)
  • Asian Institute of Gastroenterology (IN)
  • Mayo Clinic (US)
Corresponding author
Arab, Juan Pablo
ORCID
Venue
Frontiers in Medicine
Publisher
Frontiers Media SA
Published
2020-08-20
Volume
7
Pages
448-448
ISSN
2296-858X (ISSN-L)
DOI
10.3389/fmed.2020.00448
PMC
PMC7468507
OpenAlex
W3080530345
Cited by
136
References
206
Citations by year
2026: 14 · 2025: 23 · 2024: 23 · 2023: 26 · 2022: 32 · 2021: 17
FWCI
2.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Fondo Nacional de Desarrollo Científico y Tecnológico (1191145, 1200227)
  • Consejo Nacional de Innovación, Ciencia y Tecnología (AFB170005)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
non-alcoholic fatty liver disease, alcoholic liver disease, alcohol consumption, steatohepatitis, liver cirrhosis, metabolic dysfunction, obesity, metabolic syndrome, hepatocellular carcinoma, pathophysiology, disease progression

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