How parental alcohol use disorder and liver disease-related mortality influence the risk and the outcomes of alcohol-associated hepatitis (AH) in the offspring is unknown.

We analyzed data from 2 prospective observational studies of AH cases and heavy drinking controls (HDCs). Family history of parental alcohol use disorder and liver disease mortality was assessed at the study entry. Logistic regression and Cox proportional hazard models were used to assess the influences of family history on AH development and outcome.

Data from 1356 participants in two prospective cohorts (926 AH cases and 430 HDC) were combined and analyzed. Parental alcohol use disorder was found in 56.9% of AH cases and 61.1% of HDC; parental death due to liver disease was reported in 7.5% of AH cases and 5.7% of HDC. Multivariable logistic regression showed that parental liver disease-related mortality was associated with more than a doubled risk of AH development in the offspring after controlling for their demographic characteristics and drinking behavior (OR=2.26, 95% CI: [1.22, 4.20]). Moreover, among the AH cases, having a parent die of liver disease significantly increased the 90-day mortality of study participants after adjusting for the effects of other risk factors (HR=2.26, 95% CI: [1.05, 4.86]).

The study highlights the influences of parental death due to liver disease on AH development and mortality. Identifying patients at risk of AH through family history might help facilitate discussions on reducing alcohol consumption.

Advances in big data analytics, precision medicine, and artificial intelligence are transforming hepatology, offering new insights into disease mechanisms, risk stratification, and therapeutic interventions. In this review, we explore how the integration of genetic studies, multi-omics data, and large-scale population cohorts has reshaped our understanding of liver disease, using steatotic liver disease as a prototype for data-driven discoveries in hepatology. We highlight the role of artificial intelligence in identifying patient subgroups, optimizing treatment strategies, and uncovering novel therapeutic targets. Furthermore, we discuss the importance of collaborative networks, open data initiatives, and implementation science in translating these findings into clinical practice. Although data-driven precision medicine holds great promise, its impact depends on structured approaches that ensure real-world adoption.

The impact of antidiabetic and lipid-lowering medications on fibrosis in patients with metabolic dysfunction-associated steatohepatitis (MASH) is poorly understood. We evaluated associations between the use of these medications and serum liver fibrosis biomarkers, and whether they vary by genetic factors.

This cross-sectional study used baseline medication and fibrosis biomarker (aspartate aminotransferase-to-platelet ratio index [APRI], Enhanced Liver Fibrosis [ELF], Fibrosis-4 Index (FIB-4) and FibroSure/FibroTest) data from two phase 3 trials (N = 1649) of MASH with bridging fibrosis (NCT03053050, N = 785) or compensated cirrhosis (NCT03053063, N = 864). A weighted polygenic risk score (wPRS) for MASH was derived for participants of European ancestry (N = 742) using six genetic variants. Least-squares means and 95% confidence interval (CIs) were derived using multivariable linear regression.

Combined use of antidiabetic and lipid-lowering medications was associated with statistically significantly lower adjusted mean ELF (-0.34 [95% CI: -0.47, -0.20] or - 3.2%), FIB-4 (-0.53 [95% CI: -0.74, -0.32] or - 18.0%), APRI (-0.27 [95% CI: -0.37, -0.18] or - 23.1%) and FibroSure/FibroTest scores (-0.08 [95% CI: -0.11, -0.06] or - 14.7%) compared with nonuse. Among participants of European ancestry, the inverse association for FIB-4 (interaction p = 0.01) or APRI (interaction p = 0.004) was stronger in participants with high (>median) versus low (≤median) wPRS; no significant interactions were observed for ELF or FibroSure/FibroTest.

Antidiabetic and lipid-lowering medication use was associated with lower serum liver fibrosis biomarkers. Among participants with European ancestry, associations between combined use of these medications and lower FIB-4 or APRI scores were stronger in those at high genetic risk of MASH. Longitudinal studies are warranted to extend upon these potentially clinically important findings.

Patatin-like phospholipase domain-containing 3 (PNPLA3) protein 148M variant is strongly associated with cirrhosis and hepatocellular carcinoma (HCC); however, the underlying mechanisms remain elusive. This study aimed to elucidate the role of the PNPLA3148M variant in alcohol-related HCC development. Control and humanized PNPLA3148M transgenic mice were fed with an ethanol-containing diet for 12 weeks. The animals were examined for liver tumors. After the alcohol feeding, the PNPLA3148M mice had twofold higher liver cancer incidence rates and larger tumor sizes than those in the control mice. Cancer stem cell markers in the PNPLA3148M mouse livers were elevated relative to those in the control mouse livers. Alcohol detoxification was impaired in the PNPLA3148M mouse livers. Hepatic oxidative stress and DNA damage were elevated in the PNPLA3148M mice. Wnt/β-catenin and Yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (TAZ) were activated in the PNPLA3148M mouse livers. The data suggest that the PNPLA3148M variant has a strong interaction with alcohol in HCC development through attenuation of alcohol detoxification and promotion of oncogenic pathways. Targeting the PNPLA3148M variant might be useful for the prevention or treatment of alcohol-associated HCC in patients carrying this variant.

Long-term alcohol consumption is a leading global health concern, primarily due to its deleterious effects on liver function and its well-established association with hepatocellular carcinoma. Alcohol-related liver disease (ALD) encompasses a continuum-from reversible hepatic steatosis and steatohepatitis through progressive fibrosis and cirrhosis to overt hepatocellular carcinoma. Accumulating studies have revealed that the Wnt/β-catenin signaling pathway is an essential regulator in ALD pathogenesis, orchestrating diverse molecular, immunologic, and epigenetic processes. Aberrant β-catenin activity disrupts redox homeostasis, promotes chronic inflammation, drives extracellular matrix remodeling, and alters hepatocyte cell fate, thereby creating a microenvironment that is highly conducive to carcinogenesis. This article provides a systematic review of the significant function of Wnt/β-catenin signaling in ALD, emphasizing its regulatory impact on liver fat accumulation, its inflammatory role in steatohepatitis, its involvement in fibrogenesis, and its tumor-promoting effects in alcohol-related hepatocellular carcinoma. In addition, emerging therapeutic strategies that offer potential for early identification and tailored therapy of ALD are explored-including direct Wnt modulators, combinatory therapeutics, and precision medicine approaches.

Excessive alcohol use is a major risk factor for the development of an alcohol use disorder (AUD) and contributes to a wide variety of other medical illnesses, including alcohol-associated liver disease (ALD). Both AUD and ALD are complex and causally interrelated diseases, and multiple factors other than alcohol consumption are implicated in the disease pathogenesis. While the underlying pathophysiology of AUD and ALD is complex, there is substantial evidence for a genetic susceptibility of both diseases. Current genome-wide association studies indicate that the genes associated with clinical AUD only poorly overlap with the genes identified for heavy drinking and, in turn, neither overlap with the genes identified for ALD. Uncovering the main genetic factors will enable us to identify molecular drivers underlying the pathogenesis, discover potential targets for therapy, and implement patient care early in disease progression. In this review, we described multiple genomic approaches and their implications to investigate the susceptibility and pathogenesis of both AUD and ALD. We concluded our review with a discussion of the knowledge gaps and future research on genomic studies in these 2 diseases.

Alcohol-related liver disease is the third leading cause of hepatocellular carcinoma worldwide and the leading cause in Europe. Additionally, the recent definition of metabolic dysfunction-associated steatotic liver disease with increased alcohol intake (MetALD) will enrich this population with a more nuanced phenotype, reflecting recent epidemiological trends. In these patients, the hepatocellular carcinoma diagnosis is often delayed and less frequently detected through screening programmes. Moreover, at the time of diagnosis, patients with alcohol-related hepatocellular carcinoma tend to have a poorer general condition, more severely impaired liver function, and a higher prevalence of comorbidities, leading to increased competitive mortality. However, when hepatocellular carcinoma is diagnosed during surveillance programmes in patients with alcohol-related liver disease or MetALD, the rate of allocation to first-line curative treatments is high (56%) and comparable to that of patients with virus-related hepatocellular carcinoma. As a consequence, the aetiology of the underlying cirrhosis cannot be considered an independent prognostic factor in patients with hepatocellular carcinoma. Instead, prognosis is driven by liver function, general condition, and tumour burden. This underscores the crucial role of early diagnosis through periodic surveillance in patients with alcohol- or MetALD-related cirrhosis.

Advances in nucleic acid delivery have positioned the liver as a key target for gene therapy, with adeno-associated virus vectors showing long-term effectiveness in treating hemophilia. Steatotic liver disease (SLD), the most common liver condition globally, primarily results from metabolic dysfunction-associated and alcohol-associated liver diseases. In some individuals, SLD progresses from simple steatosis to steatohepatitis, cirrhosis, and eventually hepatocellular carcinoma, driven by a complex interplay of genetic, metabolic, and environmental factors. Genetic variations in various lipid metabolism-related genes, such as patatin-like phospholipase domain-containing protein 3 (PNPLA3), 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13), and mitochondrial amidoxime-reducing component 1 (MTARC1), impact the progression of SLD and offer promising therapeutic targets. This review largely focuses on genes identified through clinical association studies, as they are more likely to be effective and safe for therapeutic intervention. While preclinical research continues to deepen our understanding of genetic factors, early-stage clinical trials involving gene-based SLD therapies, including transient antisense and small-molecule approaches, are helping prioritize therapeutic targets. Meanwhile, hepatocyte gene editing technologies are advancing rapidly, offering alternatives to transient methods. As such, gene-based therapies show significant potential for preventing the progression of SLD and enhancing long-term liver health.

Excessive alcohol consumption drives the development of alcohol-associated liver disease (ALD), including steatohepatitis, cirrhosis, and hepatocellular carcinoma, and its associated complications, such as hepatorenal syndrome. Hepatocyte death, inflammation, and impaired liver regeneration are key processes implicated in the pathogenesis and progression of ALD. Despite extensive research, therapeutic options for ALD remain limited. IL-22 has emerged as a promising therapeutic target because of its hepatoprotective properties mediated through the activation of the STAT3 signaling pathway. IL-22 enhances hepatocyte survival by mitigating apoptosis, oxidative stress, and inflammation while simultaneously promoting liver regeneration through the proliferation of hepatocytes and hepatic progenitor cells and the up-regulation of growth factors. Additionally, IL-22 exerts protective effects on epithelial cells in various organs affected by ALD and its associated complications. Studies from preclinical models and early-phase clinical trials of IL-22 agonists, such as F-652 and UTTR1147A, have shown favorable safety profiles, good tolerability, and encouraging efficacy in reducing liver injury and promoting regeneration. However, the heterogeneity and multifactorial nature of ALD present ongoing challenges. Further research is needed to optimize IL-22-based therapies and clarify their roles within a comprehensive approach to ALD management. This review summarizes the current understanding of IL-22 biology and its role in ALD pathophysiology and ALD-associated complications along with therapeutic application of IL-22, potential benefits, and limitations.

Alcohol-related liver disease (ALD) is still to this date one of the leading causes of chronic liver disease globally. ALD comprises a wide disease spectrum, from the benign liver steatosis, to the life-threatening inflammatory acute phenotype of alcoholic hepatitis (AH) and ultimately, advanced liver fibrosis and cirrhosis. AH represents an acute inflammatory liver condition caused by prolonged high quantities of alcohol intake. Disease outcome varies from mild to severe, with systemic implication and high mortality. Although the pathogenesis has been extensively studied over the years, little progress has been made regarding therapeutic options. In over 50 years, steroid treatment is still the cornerstone therapeutic option, albeit having multiple limitations and a low success rate. On the other hand, important progress has been made regarding disease management and severity stratification with the implementation of different prognostic score. Although highly prevalent, AH still has many unmet needs, with a growing necessity for novel non-invasive diagnosis, prognosis biomarkers and impactful treatment options.

Primary liver cancers (PLCs) remain a major challenge to global health and an escalating threat to human life, with a growing incidence worldwide. PLCs are composed of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and mixed HCC-CCA, accounting for 85 %, 10 %, and 5 % of cases, respectively. Among the numerous identified risk factors associated with liver cancers, Alpha 1-AntiTrypsin Deficiency (AATD) genetic disease emerges as an intriguing one. AATD-related liver disease may lead to chronic hepatitis, cirrhosis, and PLCs in adulthood. Although our knowledge about the natural history of AATD-liver disease has improved recently, liver cancers associated with AATD remain poorly understood and explored, while this specific population is at a 20 to 50 times higher risk of developing PLC. Thus, we review here current knowledge about AATD-associated PLCs, describing the impact of AATD genotypes on their occurrence. We also discuss emerging hypotheses regarding the AATD PiZZ genotype-related hepatic carcinogenesis process. Finally, we perform an updated analysis of the United Kingdom Biobank database that highlights and confirms AATD PiZZ genotype as an important HCC risk factor.

The role of genetic risk factors for steatotic liver disease (SLD) is intriguing in liver transplantation (LT), as both donor and recipient genetic factors may play a role. There are only a few small-scale studies published so far.

We analysed the incidence and risk factors for post-LT SLD and the impact of 56 SLD-associated genetic variants in 595 donor-recipient pairs with liver biopsy available ≥ 6 months after LT. We evaluated whether the polygenic risk score (PRS-5) improves the ability to predict post-LT SLD in addition to non-genetic risk factors.

SLD after LT was diagnosed in 34.5% of patients during a median 7.6-year follow-up. In multivariate analysis including non-genetic risk factors, donor PNPLA3 rs738409-G (HR for SLD: C/G 1.34, p = 0.051, G/G 2.25, p = 0.004), donor HSD17B13 rs72613567-TA (HR for SLD: TA/T 0.68, p = 0.02 TA/TA HR 0.50, p = 0.10) and recipient UCP2 rs695366-G (HR for SLD: A/G 0.63, p = 0.002, G/G HR 0.50, p = 0.04) appeared as the most important genetic risk factors for post-LT SLD. The addition of PRS-5 to a multivariate regression model (including non-genetic risk factors) improved the predictive ability for SLD only modestly (AUC 0.78 to 0.80).

Various genetic variants contribute to post-LT SLD with separate variants among recipients and donors, with donor PNPLA3 rs738409-G as the most significant risk allele. Still, donor and recipient genotyping provide only modest additional value for individual risk stratification over phenotype data, highlighting the role of modifiable risk factors.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic disease and is a leading cause of advanced liver disease. We review here the genetic basis of MASLD. The genetic variants most consistently associated with hepatic steatosis implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, or mitochondrial/ER biology. The distinct mechanisms by which these variants promote hepatic steatosis result in distinct effects on cardiometabolic disease that may be best suited to precision medicine. Recent work on gene-environment interactions has shown that genetic risk is not fixed and may be exacerbated or attenuated by modifiable (diet, exercise, alcohol intake) and nonmodifiable environmental risk factors. Some steatosis-associated variants, notably those in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), are associated with risk of developing adverse liver-related outcomes and provide information beyond clinical risk stratification tools, especially in individuals at intermediate to high risk for disease. Future work to better characterize disease heterogeneity by combining genetics with clinical risk factors to holistically predict risk and develop therapies based on genetic risk is required.

Early forms of alcohol-associated liver disease (ALD) include different stages in the progression of compensated liver disease ranging from steatosis to steatohepatitis and fibrosis. ALD has been classically diagnosed at advanced stages more frequently than other liver diseases. This fact probably contributed to the scarcity of studies on early forms of ALD. Recent studies have investigated the prevalence of early ALD in the general population and have described the natural history of alcohol-induced steatosis and fibrosis, which have been linked to worse prognosis compared with early stages of other chronic liver diseases. In addition, studies on screening and early diagnosis of ALD in at-risk populations have shown that these strategies allow early detection and intervention. Of note, up to 28% of the United States population has concurrent alcohol use and metabolic syndrome, and estimated prevalence of advanced fibrosis among heavy drinkers with metabolic syndrome has increased from 3% in the 1990s to more than 10% in the 2010s. Therefore, new challenges and treatment opportunities will emerge for patients with ALD. In this review, we provide an overview of the state of the art in early ALD, focusing on natural history, diagnosis, and management, and provide insights into future perspectives.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.

Membrane contact sites between organelles are critical for the transfer of biomolecules. Lipid droplets store fatty acids and form contacts with mitochondria, which regulate fatty acid oxidation and adenosine triphosphate production. Protein compartmentalization at lipid droplet-mitochondria contact sites and their effects on biological processes are poorly described. Using proximity-dependent biotinylation methods, we identify 71 proteins at lipid droplet-mitochondria contact sites, including a multimeric complex containing extended synaptotagmin (ESYT) 1, ESYT2, and VAMP Associated Protein B and C (VAPB). High resolution imaging confirms localization of this complex at the interface of lipid droplet-mitochondria-endoplasmic reticulum where it likely transfers fatty acids to enable β-oxidation. Deletion of ESYT1, ESYT2 or VAPB limits lipid droplet-derived fatty acid oxidation, resulting in depletion of tricarboxylic acid cycle metabolites, remodeling of the cellular lipidome, and induction of lipotoxic stress. These findings were recapitulated in Esyt1 and Esyt2 deficient mice. Our study uncovers a fundamental mechanism that is required for lipid droplet-derived fatty acid oxidation and cellular lipid homeostasis, with implications for metabolic diseases and survival.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and a significant global health challenge due to its high mortality rate. The epidemiology of HCC is closely linked to the prevalence of chronic liver diseases, the predominant etiology being hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, alcohol consumption, and metabolic disorders such as metabolic dysfunction-associated steatotic liver disease (MASLD). HCC incidence varies widely globally, with the highest rates observed in East Asia and sub-Saharan Africa. This geographic disparity is largely attributed to the endemicity of HBV and HCV in these regions. In Western countries, the incidence of HCC has been rising, driven by increasing rates of alcohol abuse and the presence of steatosis liver disease. MASLD-associated HCC has a higher body mass index, a higher rate of type 2 diabetes mellitus, hyperlipidemia, hypertension, and association with cardiovascular diseases. Steatosis-associated HCC is also known to develop in the absence of cirrhosis, unlike alcohol-related liver disease and viral hepatitis. Prevention strategies vary by region, focusing on vaccination against HBV, antiviral treatments for HBV and HCV, alcohol moderation, and lifestyle interventions along with weight reduction to reduce obesity and incidence of MASLD-related HCC incidence.

Acute alcohol-associated hepatitis (AH) is a syndrome that occurs in heavy and long-term drinkers and results in severe jaundice and liver failure. The mortality rate in severe cases is 20%-50% at 28 days, and in cases that do not improve despite appropriately timed corticosteroid therapy, the mortality rate reaches 70% at 6 months. The only curative treatment is early liver transplantation, but less than 2% of patients with severe AH are eligible. In order to improve the prognosis, diagnostic tools are needed to detect appropriate cases at risk of severe conditions, and new therapies need to be developed that can replace corticosteroids. Recent research has revealed that the pathogenesis of AH involves a complex of factors, including changes in the gut microbiota, inflammatory and cytokine signalling, oxidative stress and mitochondrial dysfunction, and abnormalities in the hepatic regenerative capacity. Non-invasive diagnostic tools focusing on these specific pathologies have been reported in recent years. In addition, several novel agents targeting specific pathways are currently being developed and tested in clinical trials. This review will provide an overview of alcohol-associated hepatitis and focus on the latest diagnostic tools, particularly non-invasive biomarkers, and novel therapies.

The PNPLA3-rs738409-G variant was the first common variant associated with hepatic fat accumulation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, to date, the clinical translation of this discovery has been minimal because it has not yet been clearly demonstrated where the genetic information may play an independent and additional role in clinical risk prediction. In this mini-review, we will discuss the most relevant evidence regarding the potential integration of the PNPLA3 variant into scores and algorithms for liver disease diagnostics and risk stratification, specifically focusing on MASLD but also extending to liver diseases of other etiologies. The PNPLA3 variant adds little in diagnosing the current state of the disease, whether in terms of presence/absence of metabolic dysfunction-associated steatohepatitis or the stage of fibrosis. While it can play an important role in prediction, allowing for the early definition of risk profiles that enable tailored monitoring and interventions over time, this is most valuable when applied to populations with relatively high pre-test probability of having significant fibrosis based on either non-invasive tests (e.g. Fibrosis-4) or demographics (e.g. diabetes). Indeed, in this context, integrating FIB4 with the PNPLA3 genotype can refine risk stratification, though there is still no evidence that genetic information adds to liver stiffness determined by elastography. Similarly, in patients with known liver cirrhosis, knowing the PNPLA3 genotype can play a role in predicting the risk of hepatocellular carcinoma, while more doubts remain about the risk of decompensation.

The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established metabolic dysfunction-associated steatotic liver disease dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear.

We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity and increased IHH mRNA.

This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis, adds new insight into an established genetic locus for MASH, and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7.

Alcohol consumption is a leading cause of preventable morbidity and mortality worldwide and the primary cause of advanced liver disease. Alcohol use disorder is a chronic, frequently relapsing condition characterized by persistent alcohol consumption despite its negative consequences. Alcohol-associated liver disease (ALD) encompasses a series of stages, from fatty liver (steatosis) to inflammation (steatohepatitis), fibrosis, and, ultimately, liver cirrhosis and its complications. The development of ALD is complex, involving both genetic and environmental factors, yet the exact mechanisms at play remain unclear. Alcohol-associated hepatitis (AH), a severe form of ALD, presents with sudden jaundice and liver failure. Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD to stop the progression of the disease, making alcohol abstinence the most effective way to improve prognosis across all stages of ALD. For patients with advanced ALD who do not respond to medical therapy, liver transplantation is the only option that can improve prognosis. Recently, AH has become an early indication for liver transplantation in non-responders to medical treatment, showing promising results in carefully selected patients. This review provides an update on the epidemiology, natural history, pathogenesis, and current treatments for ALD. A deeper insight into novel targeted therapies investigated for AH focusing on new pathophysiologically-based agents is also discussed, including anti-inflammatory and antioxidative stress drugs, gut-liver axis modulators, and hepatocyte regenerative molecules.

A common genetic variant (rs738409) encoding an isoleucine to methionine substitution at position 148 in the PNPLA3 protein is a determinant of hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver-related mortality. AZD2693 is a liver-targeted antisense oligonucleotide against PNPLA3 mRNA. We evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics in single and multiple ascending dose studies.

AZD2693 was assessed in 3D cultures of homozygous PNPLA3 148M primary human hepatocytes and mice expressing human PNPLA3. The single ascending dose study investigated 2-110 mg doses in overweight/mildly obese but otherwise healthy volunteers. The multiple ascending dose study investigated three monthly doses (25 mg, 50 mg and 80 mg) in participants with MRI-proton density fat fraction (MRI-PDFF) ≥7%. Changes in liver fat content were assessed at baseline, weeks 8 and 12 by MRI-PDFF. PNPLA3 mRNA and protein knockdown levels were evaluated for the 80 mg dose.

AZD2693 potently reduced PNPLA3 expression in human hepatocytes and livers of mice. Clinically, AZD2693 was generally well tolerated (no adverse events leading to discontinuation or treatment-related serious adverse events). Half-life was 14-33 days across investigated doses. A least-square mean liver PNPLA3 mRNA knockdown of 89% and reduction of protein levels demonstrated target engagement. Changes in hepatic steatosis at week 12 were -7.6% and -12.2% (placebo-corrected least-square means) for the 25 mg and 50 mg doses, respectively. There was a dose-dependent increase of polyunsaturated fatty acids in serum triglycerides and decreases vs. placebo in high-sensitivity C-reactive protein and interleukin 6.

AZD2693 reduced liver PNPLA3 with an acceptable safety and tolerability profile. These findings support the continued development of AZD2693.

Clinical treatment options for metabolic dysfunction-associated steatohepatitis (MASH) are limited. The genetic risk factor with the largest effect size for progressing to poor liver-related outcomes in MASH is a single-nucleotide polymorphism in the gene PNPLA3 (p.I148M). In phase I single and multiple ascending dose studies, AZD2693, a liver-targeted antisense oligonucleotide, was well tolerated, reduced liver PNPLA3 mRNA and protein levels, and dose-dependently reduced liver fat content in homozygous PNPLA3 148M risk allele carriers. These data support continued development of AZD2693 as a potential precision medicine treatment for MASH. The phase IIb FORTUNA study is now ongoing.

NCT04142424, NCT04483947.

The discovery of PNPLA3 as a genetic risk factor for liver disease has transformed our understanding of the pathogenesis of alcohol-related liver disease (ALD). The recent reclassification of fatty liver disease as steatotic liver disease (SLD), introducing metabolic dysfunction and alcohol-related liver disease (MetALD), has highlighted how genetic and environmental factors synergistically drive liver damage. The PNPLA3 rs738409 variant stands as a paradigmatic example of gene-environment interaction, where its effect on liver disease is dramatically amplified by alcohol consumption, obesity and type 2 diabetes. Understanding these interactions has revealed novel pathogenic mechanisms. The robust genetic evidence and a growing understanding of molecular mechanisms have made PNPLA3 an attractive therapeutic target. Several compounds targeting PNPLA3 are now in clinical development. While initial trials have focused on metabolic dysfunction-associated SLD, the recognition that almost all individuals with excessive alcohol consumption have metabolic comorbidities provides an unprecedented opportunity to evaluate these genetically informed therapies in MetALD. In this review, we examine the role of PNPLA3 in ALD, focusing on gene-environment interactions and therapeutic implications in the context of the new disease classification framework.

An unbiased genome-first approach can expand the molecular understanding of specific genes in disease-agnostic biobanks for deeper phenotyping. TM6SF2 represents a good candidate for this approach due to its known association with steatotic liver disease (SLD).

We screened participants with whole-exome sequences in the Penn Medicine Biobank (PMBB, n >40,000) and the UK Biobank (UKB, n >200,000) for protein-altering variants in TM6SF2 and evaluated their association with liver phenotypes and clinical outcomes.

Missense variants in TM6SF2 (E167K, L156P, P216L) were associated with an increased risk of clinically diagnosed and imaging-proven steatosis, independent of the PNPLA3 I48M risk allele and hepatitis B/C (p <0.001). E167K homozygotes had significantly increased risk of SLD (odds ratio [OR] 5.38, p <0.001), steatohepatitis (OR 5.76, p <0.05) and hepatocellular carcinoma (OR 11.22, p <0.0001), while heterozygous carriers of L156P and P216L were also at an increased risk of steatohepatitis. In addition, carriers of E167K are at a 3-fold increased risk of at-risk MASH (OR 2.75, p <0.001). CT-derived liver fat scores were higher in E167K and L156P in an allele-dose manner (p <0.05). This corresponded with the UKB nuclear magnetic resonance-derived lipidomic analyses (n = 105,348), revealing all carriers to exhibit lower total cholesterol, triglycerides and total choline. In silico predictions suggested that these missense variants cause structural disruptions in the EXPERA domain, leading to reduced protein function. This hypothesis was supported by the association of rare loss-of-function variants in TM6SF2 with an increased risk of SLD (OR 4.9, p <0.05), primarily driven by a novel rare stop-gain variant (W35X) with the same directionality.

The functional genetic study of protein-altering variants provides insights on the association between loss of TM6SF2 function and SLD and provides the basis for future mechanistic studies.

The genome-first approach expands insights into genetic risk factors for steatotic liver disease with TM6SF2 being a focal point due to its known association with plasma lipid traits. Our findings validated the association of two missense variants (E167K and L156P) with increased risk of hepatic steatosis on CT and MRI scans, as well as the risk of clinically diagnosed hepatocellular carcinoma independent of the common PNPLA3 I48M risk variant. Notably, we also identified a predicted deleterious missense variant (P216L) linked to steatotic risk and demonstrated that an aggregated gene burden of rare putative loss-of-function variants was associated with the risk of hepatic steatosis. Combined, this study sets the stage for future mechanistic investigations into the functional consequences of TM6SF2 variants in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in the world and a growing cause of liver-related morbidity and mortality. Yet, at the same time, our understanding of the pathophysiology and genetic underpinnings of this increasingly common yet heterogeneous disease has increased dramatically over the last 2 decades, with the potential to lead to meaningful clinical interventions for patients. We have now seen the first pharmacologic therapy approved for the treatment of MASLD, and multiple other potential treatments are currently under investigation-including gene-targeted RNA therapies that directly extend from advances in MASLD genetics. Here we review recent advances in MASLD genetics, some of the key pathophysiologic insights that human genetics has provided, and the ways in which human genetics may inform our clinical practice in the field of MASLD in the near future.

Metabolic dysfunction-associated steatohepatitis (MASH), previously known as nonalcoholic steatohepatitis (NASH), is a multifaceted liver disease characterized by inflammation and fibrosis that develops from simple steatosis. Immune and inflammatory pathways have a central role in the pathogenesis of MASH, yet, how to target immune pathways to treat MASH remains perplexed. This review emphasizes the intricate role that immune cells play in the etiology and pathophysiology of MASH and highlights their significance as targets for therapeutic approaches. It discusses both current strategies and novel therapies aimed at modulating the immune response in MASH. It also highlights challenges in liver-specific drug delivery, potential off-target effects, and difficulties in targeting diverse immune cell populations within the liver. This review is a comprehensive resource that integrates current knowledge with future perspectives in the evolving field of MASH, with the goal of driving forward progress in medical therapies designed to treat this complex liver disease.

Heavy alcohol intake induces a wide spectrum of liver diseases ranging from steatosis, steatohepatitis, cirrhosis, and HCC. Although alcohol consumption is a well-known risk factor for the development, morbidity, and mortality of HCC globally, alcohol-associated hepatocellular carcinoma (A-HCC) is poorly characterized compared to viral hepatitis-associated HCC. Most A-HCCs develop after alcohol-associated cirrhosis (AC), but the direct carcinogenesis from ethanol and its metabolites to A-HCC remains obscure. The differences between A-HCC and HCCs caused by other etiologies have not been well investigated in terms of clinical prognosis, genetic or epigenetic landscape, molecular mechanisms, and heterogeneity. Moreover, there is a huge gap between basic research and clinical practice due to the lack of preclinical models of A-HCC. In the current review, we discuss the pathogenesis, heterogeneity, preclinical approaches, epigenetic, and genetic profiles of A-HCC, and discuss the current insights into and the prospects for future research on A-HCC. The potential effect of alcohol on cholangiocarcinoma and liver metastasis is also discussed.

New guidelines for the definitions of steatotic liver disease have named the entity of metabolic dysfunction and alcohol-associated liver disease (MetALD) as an overlap condition of metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease. There is a broad range of therapeutics in all stages of development for MASLD, but these therapeutics, in general, have not been studied in patients with significant ongoing alcohol use. In this review, we discuss the current understanding of the endogenous and exogenous risks for MASLD and MetALD. Rational strategies for therapeutic intervention in MetALD include biopsychosocial interventions, alcohol use cessation strategies, including the use of medications for alcohol use disorder, and judicious use of therapeutics for steatotic liver disease. Therapeutics with promise for MetALD include incretin-based therapies, FGF21 agonists, thyroid hormone receptor beta agonists, sodium-glucose co-transporter 2 inhibitors, and agents to modify de novo lipogenesis. Currently, glucagon-like peptide 1 receptor agonists and peroxisome proliferator-activated receptor γ agonists have the largest body of literature supporting their use in MASLD, and there is a paucity of agents in trials for alcohol-associated liver disease. From existing studies, it is not clear if unique therapeutics or a combinatorial approach are needed for MetALD. Further elucidation of the safety and benefits of MASLD-related therapies is of paramount importance for advancing therapeutics for MetALD in carefully designed inclusive clinical trials.

The large and growing burden of alcohol-associated liver disease-and the considerable burden of morbidity and mortality associated with it-has been a drive toward ongoing research into novel strategies for its treatment, with a particular focus upon alcohol-associated hepatitis (AH). Management of alcohol-use disorder forms the central pillar of alcohol-associated liver disease care, with evidence-based psychological and pharmacological approaches being well established, and certain models demonstrating improved clinical outcomes when hepatology and addiction services are co-located. Corticosteroids have previously been used somewhat indiscriminately in patients with severe AH, but effective tools now exist to assess early response (and limit futile ongoing exposure). Techniques to predict risk of corticosteroid-related infection are also available, although current clinical strategies to mitigate this risk are limited. A variety of novel therapeutic approaches to AH are at different phases of trials and evidence gathering, with some of the most promising signals related to cytokine manipulation, epigenetic modulation, and targeting of the gut microbiota (ie, by means of fecal microbiota transplant). While remaining an ongoing source of debate, early liver transplant in severe AH has grown in interest and acceptability over the past decade as evidence supporting its efficacy builds, in the process challenging paradigms about mandatory pretransplant sobriety periods. However, uncertainty remains regarding the optimal selection criteria, and whether liver transplant has a role for only a highly limited proportion of patients with AH or more widespread application. This review aims to provide an overview of this fast-moving field.

Autoimmune hepatitis (AIH) is a relatively rare autoimmune disease with a strong genetic background. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148 M (rs738409 C/G) variant has been associated with hepatic inflammation and fibrosis in chronic hepatic diseases beyond metabolic dysfunction-associated steatotic liver disease (MASLD).

Our aim was to investigate the significance of PNPLA3 I148 M variant in AIH.

Two hundred AIH patients, followed in our centre, were evaluated while 100 healthy subjects served as controls. Genotyping was performed with allelic discrimination end-point polymerase chain reaction (PCR).

The I148 M variant was present in 95/200 (47.5 %) AIH patients compared to 47/100 (47 %) healthy controls (p = 1.000). Patients with GG/CG genotypes were more likely to present with decompensated cirrhosis at diagnosis (GG/CG 6.3 % vs. CC 1 %, p = 0.039). Comorbidity with cardiometabolic risk factors and concurrence of MASLD was similar across genotypes. Simple steatosis was present in 37/186 (19.9 %) and steatohepatitis in 14/186 (7.5 %) patients with available liver biopsy without correlation with PNPLA3 genotype. Fibrosis stage and grade of inflammation were not correlated with any genotype. Response to treatment was also independent of the presence of the I148 M variant, even though a longer time was needed to achieve complete biochemical response in those carrying the GG/CG genotypes (p = 0.07). On Kaplan Meier analysis homozygosity for the G allele corelated with reduced survival free of decompensation (p = 0.006), cirrhotic events (decompensation, liver transplantation, hepatocellular carcinoma; p = 0.001) and liver-related death or liver transplantation (p = 0.011) in treated patients.

The PNPLA3 I148 M variant in AIH patients is associated with increased risk of advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related death or liver transplantation, regardless of the presence of MASLD. This signifies a potential role for the PNPLA3 I148 M variant as a new AIH biomarker allowing to identify patients at increased risk of disease progression.

Individuals with genetic polymorphisms in UGT1A1 exhibit bilirubin levels that belie their risk of liver disease (Gilbert's syndrome) but it is not known if this phenomenon extends to other common liver blood tests (LBTs).

A genome-wide association analysis of 10 LBTs was conducted using the UK biobank. Polygenic scores (PGS) were created from discordant loci (e.g. loci associated with the LBT but not associated with cirrhosis morbidity risk). Participants were assigned to a low, intermediate or high PGS for each LBT. A high PGS approximates Gilbert's syndrome (i.e. elevated LBT without an analogous increase in disease risk). The prognostic significance of an 'elevated' LBT-and how this differs by PGS-was assessed through competing risk survival analysis.

This study included 157 005 and 166 871 participants for the discovery and validation phases, respectively. Elevated LBTs were more prevalent in the high versus low PGS group, yet the 10-year risk of cirrhosis morbidity was comparable. For example, in the low PGS group, 4.3% had an elevated gamma-glutamyltransferase (GGT) and the 10-year risk of cirrhosis morbidity was .45%. Conversely, in the high PGS group, 21.2% had an elevated GGT and the 10-year risk was .38%. Accordingly, the 10-year risk of cirrhosis morbidity for individuals with an elevated GGT was markedly different in the low vs. high group (4.2% vs. 1.2%; p < .001). Similar results were apparent for Fibrosis-4 index, total bilirubin, and platelet count.

Variability in LBTs is influenced by genetic polymorphisms that have a neutral effect on disease risk. These findings have implications for interpreting elevated LBTs in clinical practice.

The growing recognition of the role of the gut microbiome's impact on alcohol-associated diseases, especially in alcohol-associated liver disease, emphasizes the need to understand molecular mechanisms involved in governing organ-organ communication to identify novel avenues to combat alcohol-associated diseases. The gut-liver axis refers to the bidirectional communication and interaction between the gut and the liver. Intestinal microbiota plays a pivotal role in maintaining homeostasis within the gut-liver axis, and this axis plays a significant role in alcohol-associated liver disease. The intricate communication between intestine and liver involves communication between multiple cellular components in each organ that enable them to carry out their physiological functions. In this review, we focus on novel approaches to understanding how chronic alcohol exposure impacts the microbiome and individual cells within the liver and intestine, as well as the impact of ethanol on the molecular machinery required for intraorgan and interorgan communication.

Alcohol-associated liver disease (ALD) is a significant global health challenge, encompassing a spectrum from steatotic liver disease to cirrhosis and alcohol-associated hepatitis, and contributed to 25% of global cirrhosis deaths in 2019. The identification of both modifiable (e.g. heavy drinking, metabolic syndromes) and non-modifiable risk factors (e.g. genetic predispositions) is crucial for effective disease management. Alcohol use assessment and treatment, by using both behavioral therapy and pharmacotherapeutic modalities, nutrition support, and optimization of liver disease modifiers, form the cornerstone of management. Advances in medical therapies, such as fecal microbiota transplantation and novel agents such as IL-22, are being explored for their therapeutic potential. A unifying theme in ALD care is the need for a personalized approach to management, accounting for the spectrum of the disease and individual patient characteristics, to tailor interventions effectively. Finally, it is essential to address the challenges to effective ALD treatment, including socioeconomic, logistical, and stigma-related barriers, to improve patient outcomes. This review discusses the current knowledge on ALD, including epidemiology, pathophysiology, risk factors, and management strategies, highlighting the critical role of integrated care models.

Recent advances in the genetics of metabolic dysfunction-associated steatotic liver disease (MASLD) are gradually revealing the mechanisms underlying the heterogeneity of the disease and have shown promising results in patient stratification. Genetic characterization of the disease has been rapidly developed using genome-wide association studies, exome-wide association studies, phenome-wide association studies, and whole exome sequencing. These advances have been powered by the increase in computational power, the development of new analytical algorithms, including some based on artificial intelligence, and the recruitment of large and well-phenotyped cohorts. This review presents an update on genetic studies that emphasize new biological insights from next-generation sequencing approaches. Additionally, we discuss innovative methods for discovering new genetic loci for MASLD, including rare variants. To comprehensively manage MASLD, it is important to stratify risks. Therefore, we present an update on phenome-wide association study associations, including extreme phenotypes. Additionally, we discuss whether polygenic risk scores and targeted sequencing are ready for clinical use. With particular focus on precision medicine, we introduce concepts such as the interplay between genetics and the environment in modulating genetic risk with lifestyle or standard therapies. A special chapter is dedicated to gene-based therapeutics. The limitations of approved pharmacological approaches are discussed, and the potential of gene-related mechanisms in therapeutic development is reviewed, including the decision to perform genetic testing in patients with MASLD.

Alcohol-associated liver disease (ALD) poses a significant risk for hepatocellular carcinoma (HCC), comprising various liver conditions from steatosis to cirrhosis. Despite accounting for a third of global HCC cases and deaths, ALD-related HCC lacks characterization compared to viral hepatitis-related HCC. Proposed mechanisms for ALD-related HCC include acetaldehyde toxicity, increased reactive oxygen species, and inflammation. This review examines ALD-associated HCC epidemiology, co-factors like viral hepatitis and metabolic syndrome, surveillance, and treatment challenges. Despite advances in screening and management, ALD-related HCC often presents at advanced stages, limiting treatment options and survival.

TM6SF2 -rs58542926-T is associated with increased cirrhosis and modestly decreased coronary artery disease prevalence. However, relative effects of TM6SF2 genotype on major adverse cardiovascular events (MACE) vs liver-related events (LRE) are not known.

We used the UK Biobank, a prospective cohort with genetic and inpatient diagnosis data. The primary predictor was TM6SF2 -rs58542926 genotype, and the primary outcomes were MACE and LRE. Effects were reported as subhazard ratios (sHRs) and 10-year cumulative incidence by Fine-Gray competing risk analyses.

More than 430,000 individuals met inclusion criteria. TM6SF2 -rs58542926-TT genotype (vs CC) was associated with higher incidence of LRE (adjusted sHR 3.16, 95% confidence interval 1.86-5.37) and lower incidence of MACE (adjusted sHR for TT vs CC genotype 0.76, 95% confidence interval 0.63-0.91). In individuals with fibrosis-4 (FIB4) < 1.3, 1.3-2.67, and > 2.67, 10-year LRE incidence in TM6SF2 -rs58542926-TT vs CC individuals was 0.08% vs 0.06% ( P > 0.05), 0.81% vs 0.20% ( P < 0.0001), and 10.5% vs 3.4% ( P = 0.00094), respectively. The corresponding values for MACE were 3.8% vs 5.1% ( P = 0.032), 6.4% vs 8.2% ( P = 0.040), and 17.1% vs 12.4% ( P > 0.05). The absolute decrease in MACE with rs58542926-TT (vs CC) genotype exceeded the absolute increase in LRE in all groups but FIB4 > 2.67. Associations of TM6SF2 genotype with LRE/MACE were significant in men but not women. TM6SF2 -rs58542926-T allele was also associated with increased hepatic steatosis and corrected T1 time by magnetic resonance imaging, with greater effect sizes in men than women.

TM6SF2 genotype has opposite effects on LRE vs MACE incidence, and absolute effects on MACE were greater except in those with highest FIB4 scores. Effects were strongest in men. These findings clarify implications of TM6SF2 genotype based on personalized clinical risk.

Chronic liver disease (CLD) represents a significant global health burden, with hepatic steatosis-associated disorders-such as metabolic dysfunction-associated steatohepatitis (MASH), alcoholic liver disease, and hepatitis C virus infection-being major contributors. Recent genome-wide association studies have identified the rs72613567:TA variant in the 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13) gene as a protective factor against the development and progression of these conditions. In this review, we summarized the current evidence surrounding the HSD17B13 rs72613567 variant, aiming to elucidate its impact on CLD risk and outcomes, and to explore the potential mechanisms behind its hepatoprotective effects. The rs72613567:TA variant induces a splice donor site mutation, resulting in a truncated, non-functional HSD17B13 protein. Numerous studies have demonstrated that this loss-of-function mutation confers protection against the development of cirrhosis and hepatocellular carcinoma (HCC) in patients with MASH, alcoholic liver disease, and hepatitis C virus infection. Moreover, the rs72613567:TA variant has been associated with reduced liver enzyme levels and improved survival in HCC patients. Integrating this variant into genetic risk scores has shown promise in predicting the progression of fatty liver disease to cirrhosis and HCC. Furthermore, inhibiting HSD17B13 expression through RNA interference and small molecule inhibitors has emerged as a potential therapeutic strategy for MASH. However, the precise molecular mechanisms underlying the hepatoprotective effects of the HSD17B13 rs72613567 variant remain to be fully elucidated. Future research should focus on clarifying the structure-function relationship of HSD17B13 and its role in liver pathophysiology to facilitate the development of targeted therapies for CLD associated with hepatic steatosis.

Observational studies have highlighted the pivotal role of inflammatory cytokines in cirrhosis progression. However, the existence of a causal link between inflammatory cytokines and cirrhosis remains uncertain. In this study, we conducted a bidirectional Mendelian randomization (MR) analysis at a summarized level to illuminate the potential causal relationship between the two variables.

This study utilized genetic variance in cirrhosis and inflammatory cytokines from a genome-wide association study (GWAS) of European descent. The MR-PRESSO outlier test, Cochran's Q test, and MR-Egger regression were applied to assess outliers, heterogeneity, and pleiotropy. The inverse variance weighted method and multiple sensitivity analyses were used to evaluate causalities. Furthermore, the validation set was used for simultaneous data validation.

The inflammatory cytokine monocyte chemoattractant protein 3 (MCP-3) was supposedly associated with a greater risk of cirrhosis. And cirrhosis was significantly correlated with increased levels of hepatocyte growth factor (HGF).

This study suggests that MCP-3 might be associated with the etiology of cirrhosis, while several inflammatory cytokines could potentially play a role in its downstream development. Additionally, the progression of cirrhosis was associated with elevated levels of HGF, suggesting a possible role for liver repair functions.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide. The risk of developing MAFLD varies among individuals, due to a combination of environmental inherited and acquired genetic factors. Genome-wide association and next-generation sequencing studies are leading to the discovery of the common and rare genetic determinants of MAFLD. Thanks to the great advances in genomic technologies and bioinformatics analysis, genetic and epigenetic factors involved in the disease can be used to develop genetic risk scores specific for liver-related complications, which can improve risk stratification. Genetic and epigenetic factors lead to the identification of specific sub-phenotypes of MAFLD, and predict the individual response to a pharmacological therapy. Moreover, the variant transcripts and protein themselves represent new therapeutic targets. This review will discuss the current status of research into genetic as well as epigenetic modifiers of MAFLD development and progression.

The investigation of dietary micronutrient intakes and risk of alcoholic liver disease (ALD) based on observational studies was limited.

Our study aimed to explore the associations of 30 dietary micronutrients intakes with risk of ALD, interactions between dietary micronutrients and genetic variation, and mediation effects of blood and urinary biomarkers on the associations between dietary micronutrients and risk of ALD.

A case-control study was conducted within the UK Biobank cohort, with 231 incident ALD cases and 1386 controls. Dietary data were collected using a dietary questionnaire that relied on a 24-h dietary recall of the previous day. Logistic regression models were employed to assess the associations of dietary micronutrient intakes with risk of ALD. We conducted stratified analyses on the associations between dietary micronutrient intakes and risk of ALD by PNPLA3 rs738409 and tested the interactions between dietary micronutrients and genetic variation. In addition, we conducted mediation analyses to investigate the mediating effects of biomarkers on the associations between dietary micronutrients and risk of ALD.

Our findings indicated significant inverse associations of thiamin, riboflavin, niacin equivalent, pantothenic acid, vitamin B-6, folate, vitamin E, calcium, magnesium, phosphorus, potassium, copper, iodine, and manganese with risk of ALD (all false discovery rate-Ptrend < 0.050). We also found a significant interaction between PNPLA3 rs738409 and magnesium (Pinteraction = 0.028). Creatinine (enzymatic) in urine, aspartate aminotransferase, and insulin-like growth factor 1 were the top 3 biomarkers with the highest number of significant mediation effects on the associations between the dietary micronutrients and risk of ALD.

Dietary intakes of thiamin, riboflavin, niacin equivalent, pantothenic acid, vitamin B-6, folate, vitamin E, calcium, magnesium, phosphorus, potassium, copper, iodine, and manganese were inversely associated with risk of ALD.