Role of Alcohol in Steatotic Liver Disease: Impact on Patients with Cardiometabolic Risk Factors

Abstract

The new definition of steatotic liver disease (SLD), as a broader concept, was a step forward in the increasing recognition of the substantial overlap between alcohol and cardiometabolic risk factors (CMRFs), in a continuum way. The spectrum of pathophysiological aspects, ranging from liver steatosis to fibrosis, has similarities in MASLD and ALD. Also, there is now considerable evidence that the association of metabolic dysfunction with increased alcohol consumption impacts on the risk of severe liver disease and prognosis. The new MetALD class, as recently proposed, shows clear differences in prognosis when comparing with MASLD and ALD groups. However, there is room for improvement, such as considering the role of previous alcohol intake, fluctuations of consumption over time, including binge drinking, refinement of alcohol assessment, and better understanding of the role of biomarkers. In summary, SLD is no doubt a significant improvement, but the new classification needs to be dynamic and adapting to patients needing frequent reassessment. Furthermore, it brings opportunities for research on the interaction between alcohol consumption and CMRFs.

Introduction

The CMRFs and hazardous alcohol consumption are among the most common etiological factors of liver disease. The rising contribution of metabolic factors is expected to more than double the burden of related advanced liver disease until 2030, in some regions of the World. [1] Until the new nomenclature joined under the umbrella term of steatotic liver disease (SLD) [2], alcohol-related liver disease (ALD), and liver disease associated with CMRFs (former non-alcoholic fatty liver disease–NAFLD) were often approached separately, thus neglecting the potential interactions of these risk factors. There is now rising evidence that alcohol and CMRFs act as synergistic co-factors for the development and progression of liver disease, influencing the prognosis, thus justifying to highlight a separate group of patients, where this overlap exists. [2] The consequent impact on clinical management of these patients is something that needs to be carefully studied in the next years.

In this review, we aimed to approach the role of alcohol in SLD, focusing on patients with CMRFs as the main drive, as well as the overlapping pathophysiology and the effect on liver disease progression, and development of hepatocellular carcinoma (HCC).

Steatotic Liver Disease: A Positive and Broaden New Nomenclature

The new umbrella term of SLD and its subclassifications, not only changed potentially stigmatizing nomenclature, but also emphasized the presence of hepatic steatosis, including a wide spectrum of causes. [2] SLD is classified into metabolic dysfunction-associated SLD (MASLD), MASLD plus increased alcohol intake (MetALD), alcohol-related liver disease (ALD), SLD with specific etiology, and cryptogenic SLD. [2]

This change implies the need to reclassify the previous non-alcoholic fatty liver disease/Non-alcoholic steatohepatitis (NAFLD/NASH) patients. However, in a large European cohort, more than 99.5% of patients with NAFLD met the MASLD criteria according to the new consensus, including the risk of overall mortality or liver-related outcomes. [3] The same was validated in an American database, with an estimated SLD prevalence of 34.2% (31.9–36.5%): MASLD 31.3%. (29.2–33.4%), MetALD 2.2% (1.6–2.9%), and ALD 0.7% (0.2–0.9%) [4]. This is important, since we can guarantee that the findings from older NAFLD studies remain valid under the new MASLD definition. [5]. Several recent studies (Table 1) showed comparable distribution of the subclassifications.

Table 1.

SLD and subtype’s prevalence in the general population

	Lee et al. [4]	Scheneider et al. [6]	Chul-Min Lee, et al. [7]	Sripongpun, et al. [8]	Kalligeros, M. et al. [9]	Petrie E. et al. [10]
Total number of patients	7367	40.189	2535	9939	9698	6901
Prevalence (%)
SLD	34.2%	27%	39%	33.2%	37.9%	34.9%
MASLD	31.3%	24%	29.4%	30%	32.5%	32.4%
MetALD	2.2%	2.1%	5.6%	2.3%	2.6%	1.5%
ALD	0.7%	0.27%	2.7%	1%	1.4%	0.8%
Etiology specific/Cryptogenic	0.03%	MASH (0.6%)	1.4%	2.8% (uncategorized)	1.2%	0.07%
Advanced fibrosis	MASLD–7.6% MetALD–5.9%	Not reported	1.46% (MASLD and MetALD)	Not reported	MASLD–8.98% MetALD–5.47%	MASLD–4.4% MetALD–2.8%
Imaging technique	Transient elastography	MRI/MRE	MRI/MRE	Ultrasonography	Transient elastography	Transient elastography
Threshold used for steatosis	CAP ≥ 288 dB	Proton density fat fraction	Proton density fat fraction (PDFF) ≥ 5%	Qualitative grading (normal, mild, moderate or severe)	CAP ≥ 263 dB	CAP ≥ 288 dB
Threshold used for advanced fibrosis	LSM ≥ 11.7 kPa	(PDFF) ≥ 5% Not reported	MRE ≥ 3.6 kPa (≥ F3)	Not reported	LSM ≥ 13.1 kPa	LSM ≥ 9.7 kPa
Alcohol assessment	Self-reported	Self-reported	Self-reported Stratified Questionnaires	Self-reported	Self-reported	Self-reported

The SLD nomenclature is based on 3 criteria: The presence of hepatic steatosis and CMRFs and/or alcohol intake (based on its quantification), in the presence or absence of other specific etiologies. These subclasses hold distinct prognosis. [11] This nomenclature has implications regarding the latest clinical practice guidelines [12] and the design of future clinical trials. (Table 2).

Table 2.

SLD and SLD subclasses in specific populations

	Isrealsen et al. [11]	Marti-Aguardo et al. [13]	Yang et al. [14]
Specific population	Current or previous excessive alcohol consumption (> 24 g/day for women and > 36 g/day for men)	Only patients with criteria for MASLD and MetALD	Prevalence in obese and overweight (20–75 years)
Total number of patients	446	2303*	539
Population (%)
SLD	72%	–	75%
MASLD	34%	97% (9% MASLD/low; 14% MASLD/mod)	67.3%
MetALD	17%	3%	4.8%
ALD	20%	–	2.6%
Advanced fibrosis/Cirrhosis	-/13%	-/7.6%	10.8%/4.5%
At-risk MASH	Not reported	14.8% (based on FAST Score ≥ 0.35)	Not reported
Assessment of liver disease	Liver biopsy	Transient elastography	MRI/MRE
Threshold used for steatosis	Histological evaluation	CAP ≥ 275 dB	Proton density fat fraction (PDFF) ≥ 5%
Threshold used for advanced fibrosis/Cirrhosis	Histological scoring	LSM ≥ 8 kPa/-	MRE ≥ 3.63 kPa/ ≥ 4.67 kPa
Alcohol assessment	Self-reported average alcohol intake in the previous 3 months	Self-reported alcohol use questionnaire for the average number of drinks consumed per week over the preceding 1 year (Low 5–9 d/w; moderate 10–13 d/w for female and 10–20 d/w in men; increase 14–35 d/w in female and 21–42 d/w in men—the same as MetALD)	Self-reported standardized validated Questionnaires (AUDIT)/lifetime drinking history questionnaire in addition to alcohol biomarkers urine ethyl glucouronide (uEtG) and blood-based phosphatidylethanol (Peth)

*Derivation cohort

Alcohol, by itself, is a promoter of hepatic steatosis and it is common to have patients presenting simultaneously with CMRFs and excessive alcohol consumption. [15] The inclusion of these patients into a different category (MetALD) creates a clearer definition and a continuum where, conceptually, the predominance of MASLD and/or ALD as dominant driver can vary, even over time. [2]

Epidemiology

Metabolic Dysfunction and Liver Disease

The association of CMRFs and liver disease has been gaining attention since the end of the past century. [16] The link of hepatic steatosis/steatohepatitis in the absence of excessive alcohol consumption, with CMRFs, often composing the metabolic syndrome, particularly insulin resistance and obesity, highlighted the possibility of a systemic disease including the liver. [17]

Previous studies, reporting to NAFLD, estimated a global prevalence of 30.05%, with South America and the Middle East being the most affected world regions. [18] The overall prevalence of cardiometabolic risk factors, estimated for MASLD and MASH populations, respectively, is: 23% and 44% are diabetic, 51% and 82% are obese, 69% and 72% have hyperlipidemia/dyslipidemia, 41% and 83% have hypertriglyceridemia and 39% and 68% have hypertension. [19]

The prediction of NAFLD increasing prevalence, can be translated to MASLD and MetALD, and correlated with the trend of increasing prevalence of the CMRFs. [20] For example, in Europe, the increasing rate of obesity match the increase in MASLD mortality, with a slight delay in peaks. [21]

MASLD patients have an increased risk of death compared to sex and age-matched reference population. [22] In these individuals the major cause of death is not liver-related, but cardiovascular diseases (CVD)-related. [22] The CVD-specific mortality in MASLD is estimated to be 4.79 per 1,000 person-years, six times higher than the liver-specific mortality. [19] This finding correlates with the increased prevalence and incidence of atherosclerotic cardiovascular disease in these individuals. [23] Furthermore, the link of metabolic associated liver disease with CVD, probably acts as an independent risk factor, based on the increased long-term risk of fatal and non-fatal CVD in individuals with more severe liver disease. [24] Considering liver-related mortality, the incidence rate of MASLD was only 0.77 per 1,000 person-years comparing with increases in more advanced liver disease. [19] It is important to point out, that the risk of all-cause and liver-related mortality increases substantially with the progression of fibrosis stage. [25]

Recently, SLD has been increasing in its health impact, along with growing awareness of the associated economic burden. [26] This awareness is not limited to the hepatology field and extends to other fields, highlighting the clinical importance of early detection in order to provide early and appropriate lifestyle measures and pharmacological interventions to prevent both liver-related and CVD-related complications. [27]

Alcohol Consumption and Liver Disease

Alcohol is a leading risk factor for both death and disability-adjusted life years (DALY’s) globally, and the safest level of drinking is none. [28] One major problem in the field of alcohol-related disease is the lack of universal reporting of the amount of alcohol in a standard drink. In fact, the amount of alcohol in a standard drink can vary from 8 to 14 grs in different countries, and it would probably be better to use the amount of alcohol in grs/ per week (to account for binge weekend alcohol consumption). More so, fluctuations of alcohol consumption in a lifetime make the evaluation of the alcohol consumption particularly difficult. Furthermore, the determination of alcohol harm is difficult, due to its multiple mechanisms (adverse effects on organs and tissues; acute intoxication; dependent drinking leading to impairments and potentially self-harm or violence), pattern of drinking and consumed volume determination. [28] The global number of deaths caused by alcohol was about 3 million in 2016, with the highest proportion being attributed to alcohol-related digestive diseases. [29]

The role of alcohol as a promoter of liver disease is well known, including the relation between alcohol consumption and liver-specific cause mortality. [30] The overall prevalence of alcohol-related liver disease (ALD) was estimated to be 4.8% in a recent meta-analysis, with strong male predominance, more than double that of females. [30] Europe is the region with the highest prevalence (5.4%) [30], in parallel with having the highest alcohol consumption per-capita. [21] The ALD population have an increased mortality compared to the general population, even in the absence of cirrhosis. [31]

In relation to the pattern of consumption, the risk of ALD appears to be higher in daily drinkers compared to less frequent drinkers, when alcohol amount was taken into account. [32] However the role of binge drinking remains controversial with data pointing in different directions, associating binge drinking with liver disease risk after adjustment for average daily alcohol intake and age. [33, 34] The duration of consumption, although difficult to study, appears to be also relevant in the progression of liver disease. [35]

In ALD, the most common cause of death is related to liver disease itself, accounting for more than 40% of all deaths. [31] The risk of non-liver related causes of death is also increased compared to the general population, with a 2.2-fold increase for CVD-specific mortality and 3.2-fold increased risk of death from extra-hepatic malignancies. [31] Patients in cirrhotic stage have the worst prognosis, although there has been some mortality improvement in the last decades. [36, 37] Despite the positive trend, these patients still have an average life expectancy 14–16 years shorter than the general population. [37]

Interaction Between Alcohol and Cardiometabolic Risk Factors

From Hepatic Steatosis to Hepatic Fibrosis

The spectrum of liver pathology, ranging from simple steatosis or steatosis accompanied by inflammation (steatohepatitis) to scar tissue formation (fibrosis) has a significant overlap between alcohol and CMRFs. [38]

Innate immune system and oxidative stress caused by gut-derived endotoxins play a key role in ALD. [39] There is considerable evidence about the role of chronic alcohol intake in inducing changes in the intestinal microbiota composition, and their contribution to disease progression. [40] In a simplified view, alcohol-induced hepatocellular damage occurs as a direct effect of alcohol and its metabolites and because of endotoxin translocation, facilitated by a reduction of reticuloendothelial system (RES), especially by Kupffer cells in ALD. [39] Ingestion of alcohol leads to increased production of reactive oxygen species (ROS), which are generated during metabolism of alcohol by cytochrome P450 2E1 enzyme. [41]

In the metabolic dysfunction pathway, the key factor is insulin resistance, associated to conditions like obesity, diabetes, and dyslipidemia, that promote the fat accumulation on liver. [38] Some hypotheses have been proposed to explain the pathophysiological mechanisms that promote the progression from simple hepatic steatosis to steatohepatitis, like the “two hit theory.” [42] This model considered the development of steatosis to be the ‘first hit’ increasing the sensitivity of the liver to ‘second hits’ leading to hepatocyte injury, that can be promoted by oxidative stress, associated CYP2E1 induction and cytokines, predominantly TNF-α. [38] In fact, the induction of CYP2E1 is associated with the pathogenesis of ALD as well as with obesity, type 2 diabetes, and hyperlipidemia. [38] Nonetheless, there remains a knowledge gap in understanding why only a minority of patients with classical risk factors for MASLD or excessive alcohol consumption progress beyond simple steatosis. (Fig. 1).

Fig. 1.

The spectrum of steatotic liver disease, disease modifiers, and the main causes of morbidity and mortality across the disease spectrum

There is a clear overlap in the main pathophysiological aspects, with the exception of direct alcohol-related mechanisms, acting as added factors in the presence of CMRFs. [43] Consequently, the histological characteristics of MASH resemble those of alcoholic steatohepatitis. Although some aspects are unique for MASLD and others for ALD, the distinction between them is often challenging. [44] For this reason, the term steatohepatitis followed by the underlying clinical dominant driver (CMRFs and/or alcohol consumption) seems more appropriate to use as histopathological diagnosis have difficulties differentiating the main driver. [45] These aspects further support approaching SLD as an umbrella disorder, with a spectrum of causes ranging from pure MASLD to ALD. However, it must be recognized that some patients may have alcohol consumption, CMRFs and fibrosis in the absence of steatosis.

Alcohol Consumption in Patients with Cardiometabolic Risk Factors: Impact on Liver Disease Prognosis

There is now considerable evidence that the combination of metabolic dysfunction and increased alcohol consumption, the primary drivers of MASLD and ALD, respectively, affects the risk of severe liver disease. [15] Additionally, genetics and gut microbiota appears to play a role as disease modifier in SLD patients. [46] However, one of the key questions, and object of controversy, is what would be a safe threshold for the amount of weekly alcohol consumption if any?

Previous studies have suggested that mild alcohol consumption does not induce steatosis and can even be a protective factor of NAFLD/NASH, [47–50] with others pointing in the opposite direction. [15, 51] In cardiovascular field, some studies also suggested a potential cardio-protective effect of low amount of alcohol, partially due to the impact in common risk factors with MASLD. [52, 53] These considerations were beyond the cutoff definition (daily alcohol consumption up to 30 g in men and/or 20 g in women) of previous NAFLD guidelines. [54–56] When considering the potential harm of alcohol, only ischemic cardiac events show a j-curve mortality. In contrast, for all other health outcomes, including liver disease, only zero alcohol consumption is entirely safe. [28] There is no protective effect against cirrhosis at any level of drinking compared to long-term abstinence, particularly in women. [57] It is important to highlight that there is no prospective randomized trials on moderate alcohol use in MASLD and most data derive from observational studies and population databases. However, when comparing prognosis according to the different subclasses, a very recent study has shown that the risk of decompensation increases in a stepwise manner from MASLD, through MetALD to ALD, in parallel with overall mortality, independent of age, sex, and liver stiffness. [11] The data concerning patients with alcohol consumption above previous mentioned cutoff is more robust and less controversial. A large national wide survey in United States (NHANES III) including more that 4000 adults with hepatic steatosis, showed that the presence of excessive alcohol consumption and metabolic syndrome were both associated with increased mortality in these patients. [58] Furthermore, the association of excessive alcohol consumption with mortality was significant only in individuals with metabolic syndrome, although the authors justify that with sample size, that could not be large enough to capture milder effects which could still exist for lower amounts of alcohol. [58]

In a Finish national cohort study, the individuals considered to be alcohol risk users (> 210 g/week for men, > 140 g/week for women—the actual cutoff values to exclude MASLD) and have diabetes, have higher rates of progression to cirrhosis than patients with only a high alcohol consumption. [15] This study also reinforces the idea of no safe threshold, because even those fulfilling criteria for MASLD (NAFLD in the study) showed increased risk of liver-related events (hospitalization due to liver disease, liver-related death or a diagnosis of HCC) if they consume any alcohol amount. [15]

In another recent large population cohort study, including more than 1.1 million US veterans with SLD, 1 in 9 patients reported high-risk alcohol use, what was associated with 43% higher risk of cirrhosis. [59]

One of the possible confusing elements prior to the new nomenclature, is the misclassification of some patients as MASLD that in fact had ALD, or vice-versa. That was explored in a population-based cohort study in Sweden with data from National Patient Registry, showing that 17% of patients with a formal diagnosis of MASLD, at some point in life also had a diagnosis of ALD. [60] The study also found that this particular group of patients have a higher risk of progression to cirrhosis and HCC. [60] We can postulate that part of these patients, using the new nomenclature, could be have been classified at some point as MetALD, also highlighting a distinct prognosis when comparing to “pure” MASLD patients as well as the importance of previous alcohol consumption. Alcohol by itself is a stronger driver to fibrosis and liver disease severity than cardiometabolic risk factors individually, increasing the risk of cirrhosis in SLD patients. [59]

Furthermore, even in MASLD/MetALD category, there is a direct relationship between the number of CMRFs and/or number of alcohol units consumed, allowing the stratification of these patients at different levels in terms of progression to significant fibrosis. [61] Fibrosis increased as alcohol intake and the number of cardiometabolic risk factors rise, ranging from 2.2% in patients with one risk factor and very low alcohol consumption to 28.6% in those with four to five risk factors and MetALD. [61] As expected, the prognosis for MetALD fall between MASLD and ALD, with ALD having the highest mortality risk when compared to non-SLD population. [8]

The difference in outcomes among SLD are not solely related to liver-related morbidity and mortality. In MetALD patients, cause-specific mortality may follow the pattern of MASLD (more CVD-related) or ALD (more liver-related mortality) depending on the level of alcohol exposure. [8] Also, there is some evidence that individuals with MetALD, due to significant alcohol consumption, could have a higher risk of cardiovascular disease than those with MASLD, suggesting that higher alcohol consumption may further elevate the risk in individuals with existing cardiometabolic risk factors. [62]

Risk of Hepatocellular Carcinoma

Liver cancer is the sixth most common cancer and the third leading contribution for cancer-related death globally with hepatocellular carcinoma (HCC) comprising 75–85% of primary liver cancer cases. [63] The risk of HCC is higher in patients with cirrhosis from any etiology with an annual incidence ranging from 1 to 4% [64], what warrants these patients to surveillance programs. [65, 66] In clinical practice, MASLD patients are particularly challenging because HCC develops in non-cirrhotic patients, corresponding to 20–30% of MASLD-related HCCs cases. [67, 68] This risk can be partially explained by the important role of cardiometabolic risk factors associated with MASLD/MetALD, that are known risk factors for several extra hepatic-malignancies and are independent risk factors for HCC, like diabetes mellitus [69–73], and obesity. [74–76]

Alcohol is known to increase the risk of liver cancer, [77] although some studies have showed lack of association with moderate drinking (less that 3 drinks per day). [78] Beyond variation in cutoff levels, previous studies have shown that even at social alcohol consumption can increase hepatocarcinogenesis risk in patients with steatosis and known CMRFs. [79, 80] Notably, despite the low level of evidence, even minimal alcohol consumption can increase HCC risk in this specific population, particularly in those with advanced fibrosis. [81] The data regarding alcohol can support a potentially significant difference in HCC risk of patients with MetALD, versus the MASLD. [60] Further studies are needed using the new nomenclature.

Pitfalls and Opportunities in Current MetALD Definition

Since the release of the new SLD nomenclature, several studies aiming to evaluate MetALD prevalence among SLD population, found a range from 2 to 10%. [4, 6, 9, 62, 82] Most of these studies were based on population databases and non-invasive tests to access the existence of steatosis/fibrosis. When considering only those with current or past alcohol consumption, the prevalence rises to 24%, highlighting this group as one of particular interest. [11]

One of the questions concerns how dynamic the SLD subclasses are over time, when focusing solely on alcohol consumption, the variation can be significant, making it challenging to capture in cohort studies. [32, 83] These variations over time, even in short-term, cannot be ignored and need further study. This could significantly impact clinical trials and practice. If we focus solely on alcohol consumption cutoffs, a patient classified as MetALD today could be classified as MASLD or ALD within a year, so the definition should be dynamic, as the new nomenclature consensus refers to the current pattern of alcohol consumption, without consideration of historical alcohol use for patients who achieved abstinence from alcohol. [2]

Several problems remain regarding alcohol cutoffs. There is significant heterogeneity in evaluating alcohol consumption. Additionally, consumption between zero and low-risk cutoff values has not been shown to have a similar effect on liver disease risk. On the other end of the spectrum, it is yet to be confirmed whether there is a threshold above which alcohol is so significant that the impact of any CMRFs becomes negligible, challenging the proposed cutoff of 50–60 g/d for distinguishing for MetALD and ALD.

Underreporting of alcohol consumption could misclassify these patients as having MASLD or MetALD. In fact, the evaluation of alcohol consumption objectively remains a central problem, and the methods used, very much differ between studies, which must be taken into consideration when interpreting the available evidence. The inaccuracies in measuring alcohol consumption, are also affected by the absence of an universal agreement about the amount of alcohol in a standard drink. For example, in British recommendations the standard unit contains 8 g of pure alcohol, in United Sates the value is higher with 14 g, and even inside Europe the definition can vary on a country level. [84, 85] The assessment of alcohol consumption should be based on direct interviewing, questionnaires (like AUDIT-c test [86]), although they are rather cumbersome. Biomarkers (specific and non-specific, like phosphatidylethanol—Peth will probably be increasingly important in the field, in particular to classify patients as MetALD, since results are more objective. This can be of great importance, especially in clinical trials. [87] Collectively, it’s possible that we can be underestimating the true prevalence of MetALD and ALD patients, but will be difficult to counterbalance that, especially on a population level when alcohol consumption will always be always dynamic. Some improvement should be made with the uniformization of the standard drink reference and definition of an interval of time for consumption/abstinence.

Furthermore, we still do not know after abstinence or significant reduction of alcohol consumption how long does it take to normalize the risk, or if it will ever happen. Also, considering that more than 90% of ALD patients have at least one cardiometabolic risk factor [8, 88], by the current definition we would be probably classifying past heavy drinkers as MASLD or MetALD, although in clinical practice we used to continue to classified with ALD, specially does with advanced fibrosis/cirrhosis. The data we have on ALD shows that complete abstinence improves survival for patients after the initial diagnosis compared to patients who continued to drink, no matter whether ALD was early/compensated or decompensated, but the long-term prognosis was only determined by fibrosis stage. [89]

Another question that should be raised is the importance of the number and kind of CMRFs in the risk and progression of SLD. As previously mentioned, obesity and diabetes appear to be stronger drivers than dyslipidemia or hypertension alone. On the other hand, the number of factors influences the cumulative risk, and as showed by Marti-Aguado et al., this is important in predicting the risk of significant fibrosis, as patients with 4 to 5 CMRFs and alcohol consumption inside MASLD cutoffs have more risk than a MetALD patient with 1 or 2 cardiometabolic risk factors. [61] Consequently, algorithms combining cardiometabolic risk factors and alcohol consumption cutoffs may be of great interest to predict risk of progression.

The awareness of the additional risk of hazardous alcohol consumption can promote a more active screening of SLD patients and metabolic risk factors, as shown in previous studies of NAFLD-MAFLD. [87] The same applies in the opposite direction, by actively screening for CMRFs in ALD. It is important to approach these patients in a holistic manner, as the 3 criteria for SLD (hepatic steatosis and/or CMRFs and/or alcohol intake) are not in a closed box, and additional factors like exercise, diet, and/or sleep could play a role on the substantial variation of individual susceptibility. [90, 91]

Lifestyle intervention as Mediterranean diet and regular exercise are the cornerstone of treatment for patients with MASLD, which can also be applied to MetALD patients. [12, 54] Recently, resmetiron (a liver-directed thyroid hormone receptor beta-selective agonist) became the first FDA-approved drug for MASH patients, although the trial excluded patients with MetALD criteria, so the potential benefit in these patient population is unclear. [92] There are medications that although approved for other indications demonstrated benefits for MASH in clinical trials and should be considered when other indications are present. [12, 54, 93–97] In ALD, the goal is always complete alcohol abstinence in order to hold or reduce disease progression and improve prognosis, and that should apply also to MetALD patients. The new perspectives in the therapeutic field, can rely on drugs acting on both CMRFs and alcohol intake. For example in mice, semaglutide (GLP-1 analogue) showed potential in reducing alcohol consumption by modulating central GABA neurotransmission. [98] Similarly, this potential was observed in humans with both semaglutide and tirzapatide. [99] On the other hand, bariatric surgery in MetALD patients with obesity should be carefully assessed, as previous studies showed an increased risk of alcohol use disorder post-bariatric surgery. [100–102]

Conclusion

The subclassification inside the SLD umbrella has great future potential for new lines of investigation and change the awareness about alcohol consumption and his interaction with CMRFs. There is no doubt that the subclasses are clinically relevant, as showed by clear differences in prognosis. Nonetheless, there is still room for improvement, especially considering the role of previous alcohol intake, window of assessment, refinement of alcohol cutoffs, and potential role of alcohol consumption biomarkers. The SLD classification should be a dynamic spectrum, with patients needing frequent reassessment. Finally, regarding management of SLD, our main focus should be on controlling the risk factors either alcohol consumption or CMRFs. The role of the new treatments under study needs to be carefully evaluated regarding the severity of the disease and their potential contribution to abrogate the risk factors, including excessive alcohol consumption.

Abbreviations

AASLD

American Association for the Study of Liver Disease

ALD

Alcohol-Related Liver Disease

CVD

Cardiovascular Diseases

CMRFs

Cardiometabolic Risk Factors

DALY’s

Disability-Adjusted Life Years

HCC

Hepatocellular Carcinoma

MASH

Metabolic Dysfunction-Associated Steatohepatitis

MASLD

Metabolic Dysfunction-Associated Steatotic Liver Disease

MetALD

MASLD with Increased Alcohol Intake

NAFLD

Non-Alcoholic Fatty Liver Disease

NASH

Non-Alcoholic Steatohepatitis

RES

Reticuloendothelial System

ROS

Reactive Oxygen Species

SLD

Steatotic Liver Disease

TNF

Tumor Necrosis Factor

Author Contributions

All the authors made substantial contributions to the article. All authors critically revised the manuscript. All authors have approved the final version of the manuscript.

Funding

Open access funding provided by FCT|FCCN (b-on). This review had no funding resources.

Data Availability

No datasets were generated or analyzed during the current study.

Declarations

Conflict of interests

HCP–Lectures and advisory board fees from Orphalan, Novo Nordisk, EISAI and Advanz Pharm.