Understanding the impact of non-alcoholic steatohepatitis with metabolic comorbidities on adults: a real-world qualitative study.

OBJECTIVE: Limited real-world evidence exists to better understand the patient experience of living with symptoms and impacts of non-alcoholic steatohepatitis (NASH). This study aimed to (1) describe patient-reported perspectives of NASH symptoms and impacts on patients' daily lives and (2) develop a patient-centered conceptual NASH model. METHODS: A cross-sectional study using semi-structured qualitative interviews was conducted among adults (≥18 years) in the United States living with NASH. Eligible participants were diagnosed with NASH, had mild to advanced fibrosis (F1-F3), and no other causes of liver disease. The interview guide was informed by a targeted literature review (TLR) to identify clinical signs, symptoms, impacts, and unmet treatment needs of NASH. Participants described their experiences and perspectives around NASH and the symptoms, symptom severity/bother, and impact of NASH on their daily activities. Interviews were audio-recorded and transcribed verbatim for coding and thematic analysis. RESULTS: Twenty participants (age: 42.4 years; female: 50.0%) were interviewed. Participants discussed their experience with NASH symptoms (most frequent: fatigue [75.0%]; weakness/lethargy [70.0%]) and impacts (most frequent: physical and psychological/emotional [70.0% each]; dietary [68.4%]). Participants considered most symptoms to be moderately severe or severe and moderately or highly bothersome. Findings from the TLR and qualitative interviews were incorporated into a conceptual model that describes patient-reported symptoms and impacts of NASH, clinical signs, risk factors, and unmet treatment needs. CONCLUSION: Our study provides insights into patients' perspectives of NASH symptoms and their impact on their daily lives. These findings may guide patient-physician conversations, supporting patient-centered treatment decisions and disease management.

Study findings help to address the gap in current literature about patients' perspectives on NASH and its symptoms as well as its impact on daily life.The study proposes a holistic conceptual model that describes patients' perspectives of living with NASH, including symptoms and their impact, the clinical signs and risk factors of NASH, and the unmet treatment needs of the disease.Healthcare providers can use study findings to inform patient-focused decisions around treatment strategies for NASH.

The Global Epidemic of Metabolic Fatty Liver Disease.

PURPOSE OF REVIEW: The objective of this manuscript is to examine the current literature on the epidemiology of metabolic dysfunction-associated steatotic liver disease (MASLD), its correlation with cardiovascular disease (CVD) outcomes, as well as to evaluate the update in nomenclature from non-alcoholic liver disease (NAFLD). RECENT FINDINGS: The update of diagnostic criteria from NAFLD to MASLD reduces the stigma associated with alcohol consumption and poor health choices. It also shines a light on the crucial role of cardiometabolic risk factors in disease pathophysiology. The incidence and prevalence of MASLD are projected to increase significantly in the future as the population burden of cardiometabolic risk factors rises. MASLD is also a potent risk factor for developing CVD that should be tackled by using a multi-disciplinary team with a holistic approach. As the new nomenclature for metabolic liver disease is adopted on a global scale, more research is needed to investigate the applicability of findings from previous trials focusing on NAFLD. It is anticipated that the epidemic of MASLD will continue to increase globally, hence the urgent need for therapeutic approaches to reverse this trend.

Vitamin E intake is inversely associated with NAFLD measured by liver ultrasound transient elastography.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, whose severe form is associated with oxidative stress. Vitamin E as an antioxidant has a protective potential in NAFLD. Whether dietary intake of vitamin E, supplementary vitamin E use, and total vitamin E have a preventive effect on NAFLD requires investigation. A cross-sectional study used data from the National Health and Nutrition Examination Survey (2017-2020) was conducted. Vitamin E intake, including dietary vitamin E, supplementary vitamin E use, and total vitamin E, was obtained from the average of two 24-h dietary recall interviews. The extent of hepatic steatosis was measured by liver ultrasound transient elastography and presented as controlled attenuated parameter (CAP) scores. Participants were diagnosed with NAFLD based on CAP threshold values of 288 dB/m and 263 dB/m. The statistical software R and survey-weighted statistical models were used to examine the association between vitamin E intake and hepatic steatosis and NAFLD. Overall, 6122 participants were included for NAFLD analysis. After adjusting for age, gender, race, poverty level index, alcohol consumption, smoking status, vigorous recreational activity, body mass index, abdominal circumference, hyperlipidemia, hypertension, diabetes, and supplementary vitamin E use, dietary vitamin E was inversely associated with NAFLD. The corresponding odds ratios (OR) and 95% confidence intervals (CI) of NAFLD for dietary vitamin E intake as continuous and the highest quartile were 0.9592 (0.9340-0.9851, P = 0.0039) and 0.5983 (0.4136-0.8654, P = 0.0091) (Ptrend = 0.0056). Supplementary vitamin E was significantly inversely associated with NAFLD (fully adjusted model: OR = 0.6565 95% CI 0.4569-0.9432, P = 0.0249). A marginal improvement in total vitamin E for NAFLD was identified. The ORs (95% CIs, P) for the total vitamin E intake as continuous and the highest quartile in the fully adjusted model were 0.9669 (0.9471-0.9871, P = 0.0029) and 0.6743 (0.4515-1.0071, P = 0.0538). Sensitivity analysis indicated these findings were robust. The protective effects of vitamin E significantly differed in the stratum of hyperlipidemia (Pinteraction < 0.05). However, no statistically significant results were identified when the threshold value was set as 263 dB/m. Vitamin E intake, encompassing both dietary and supplemental forms, as well as total vitamin E intake, demonstrated a protective association with NAFLD. Augmenting dietary intake of vitamin E proves advantageous in the prevention of NAFLD, particularly among individuals devoid of hyperlipidemia.

The association of the healthy food diversity index with the risk of non-alcoholic fatty liver disease among the adult population.

BACKGROUND AND AIM: Dietary diversity index is a useful evaluation index for examining the role of dietary pattern in predicting chronic diseases risk, including non-alcoholic fatty liver disease(NAFLD). In the present study, we aimed to examine the possible association of dietary diversity using US Healthy Food Diversity(US HFD) index and the NAFLD risk in Iranian adults. METHODS: A total of 675 individuals (225 patients with NAFLD and 450 controls) aged 20-60 years were recruited for the current case-control study. Data on dietary intakes were determined using a validated food frequency questionnaire, and dietary diversity was calculated using the US HFD index. In patients with NAFLD, an ultrasound scan of the liver was used to detect NAFLD. Logistic regression models were used to estimate the odds ratios(ORs) and 95 % confidence interval(CI) of NAFLD across tertiles of the US HFD index. RESULTS: Mean ± SD age of the study population were 38.13 ± 8.85 years. The median (interquartile) score of the US HFD index in patients with NAFLD and healthy subjects was 0.08(0.07-0.09) and 0.09(0.08-0.10), respectively. In the age and sex-adjusted model, the odds of NAFLD were considerably reduced across tertiles of the US HFD index (OR:0.48; 95%CI:0.32-0.72, Ptrend<0.001). Also, in the final model, after adjusting for age, sex, waist-to-hip ratio, smoking, physical activity, marital status, socioeconomic status, and energy intake, the odds of NAFLD were significantly reduced across tertiles US HFD index (OR:0.55; 95%CI:0.31-0.97, Ptrend<0.001). Furthermore, for each SD increase in the US HFD index, the odds of NAFLD are reduced by 23 % (OR:0.77;95%CI:0.60-0.97,P-Value<0.001). CONCLUSIONS: Our findings revealed that greater adherence to dietary pattern with a high US HFD score, defined by higher intakes of fruits, vegetables, whole grains, legumes, nuts, low-fat dairy, seeds, soya products, and plant oils may be related to reducing the odds of NAFLD.

Genetically predicted plasma levels of amino acids and metabolic dysfunction-associated fatty liver disease risk: a Mendelian randomization study.

BACKGROUND: Emerging metabolomics-based studies suggested links between amino acid metabolism and metabolic dysfunction-associated fatty liver disease (MAFLD) risk; however, whether there exists an aetiological role of amino acid metabolism in MAFLD development remains unknown. The aim of the present study was to assess the causal relationship between circulating levels of amino acids and MAFLD risk. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using summary-level data from genome-wide association studies (GWAS) to evaluate the causal relationship between genetically predicted circulating levels of amino acids and the risk of MAFLD. In the discovery MR analysis, we used data from the largest MAFLD GWAS (8434 cases and 770,180 controls), while in the replication MR analysis, we used data from a GWAS on MAFLD (1483 cases and 17,781 controls) where MAFLD cases were diagnosed using liver biopsy. We used Wald ratios or inverse variance-weighted (IVW) methods in the MR main analysis and weighted median and MR-Egger regression analyses in sensitivity analyses. Furthermore, we performed a conservative MR analysis by restricting genetic instruments to those directly involved in amino acid metabolism pathways. RESULTS: We found that genetically predicted higher alanine (OR = 1.43, 95% CI 1.13-1.81) and lower glutamine (OR = 0.83, 95% CI 0.73-0.96) levels were associated with a higher risk of developing MAFLD based on the results from the MR main and conservative analysis. The results from MR sensitivity analyses and complementary analysis using liver proton density fat fraction as a continuous outcome proxying for MAFLD supported the main findings. CONCLUSIONS: Novel causal metabolites related to MAFLD development were uncovered through MR analysis, suggesting future potential for evaluating these metabolites as targets for MAFLD prevention or treatment.

Global trends and hotspots of treatment for nonalcoholic fatty liver disease: A bibliometric and visualization analysis (2010-2023).

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is chronic, with its progression leading to liver fibrosis and end-stage cirrhosis. Although NAFLD is increasingly common, no treatment guideline has been established. Many mechanistic studies and drug trials have been conducted for new drug development to treat NAFLD. An up-to-date overview on the knowledge structure of NAFLD through bibliometrics, focusing on research hotspots, is necessary to reveal the rational and timely directions of development in this field. AIM: To research the latest literature and determine the current trends in treatment for NAFLD. METHODS: Publications related to treatment for NAFLD were searched on the Web of Science Core Collection database, from 2010 to 2023. VOSviewers, CiteSpace, and R package "bibliometrix" were used to conduct this bibliometric analysis. The key information was extracted, and the results of the cluster analysis were based on network data for generating and investigating maps for country, institution, journal, and author. Historiography analysis, bursts and cluster analysis, co-occurrence analysis, and trend topic revealed the knowledge structure and research hotspots in this field. GraphPad Prism 9.5.1.733 and Microsoft Office Excel 2019 were used for data analysis and visualization. RESULTS: In total, 10829 articles from 120 countries (led by China and the United States) and 8785 institutions were included. The number of publications related to treatment for NAFLD increased annually. While China produced the most publications, the United States was the most cited country, and the United Kingdom collaborated the most from an international standpoint. The University of California-San Diego, Shanghai Jiao Tong University, and Shanghai University of Traditional Chinese Medicine produced the most publications of all the research institutions. The International Journal of Molecular Sciences was the most frequent journal out of the 1523 total journals, and Hepatology was the most cited and co-cited journal. Sanyal AJ was the most cited author, the most co-cited author was Younossi ZM, and the most influential author was Loomba R. The most studied topics included the epidemiology and mechanism of NAFLD, the development of accurate diagnosis, the precise management of patients with NAFLD, and the associated metabolic comorbidities. The major cluster topics were "emerging drug," "glucagon-like peptide-1 receptor agonist," "metabolic dysfunction-associated fatty liver disease," "gut microbiota," and "glucose metabolism." CONCLUSION: The bibliometric study identified recent research frontiers and hot directions, which can provide a valuable reference for scholars researching treatments for NAFLD.

Association between use of vitamin and mineral supplement and non-alcoholic fatty liver disease in hypertensive adults.

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic metabolic disorder in hypertensive adults. Impaired metabolism of micronutrients may increase NAFLD risk by exacerbating oxidative stress, insulin resistance, and inflammation among hypertensive adults. In this first cross-sectional analysis of 7,376 hypertensive adults with 2,015 NAFLD cases in the Korea National Health and Nutrition Examination Survey, vitamin and mineral supplements (VMS) use was identified via questionnaire. NAFLD was defined by a hepatic steatosis index > 36. Multivariable-adjusted odds ratios (MVOR) and 95% confidence intervals (CIs) were calculated using logistic regression models. In our study, 18.6% were current users of VMS; of these, 76.7% used multi-vitamin/mineral supplements. Current VMS users had significantly lower odds of NAFLD, compared with non-users (MVOR [95% CI]: 0.73 [0.58-0.92]). The inverse association became attenuated and non-significant among those consuming VMS at higher frequency (≥ 2 times/day), for longer duration (> 16 months), and taking ≥ 2 VMS products. The inverse association with current use of VMS was only evident in those aged < 56 years (MVOR [95% CI]: 0.54 [0.40-0.72]) and men (MVOR [95% CI]: 0.56 [0.40-0.80])(Pinteraction ≤ 0.04). Our results suggest that VMS use may lower NAFLD risk, particularly among younger or male hypertensive adults, if taken in moderation.

Association between equol and non-alcoholic fatty liver disease in Japanese women in their 50s and 60s.

BACKGROUND AND AIM: Equol is a metabolite of soy isoflavone and has estrogenic activity. The incidence of non-alcoholic fatty liver disease (NAFLD) increases after menopause in women, which is thought to result in a decrease in estrogen. This study aimed to evaluate the association between equol and NAFLD. METHODS: We evaluated 1185 women aged 50-69 years who underwent health check-ups at four health centers in Fukushima, Japan. Equol producers were defined by a urinary equol concentration of 1.0 µM or more. In addition to comparison between equol producers and non-producers, the association between equol and NAFLD was estimated using logistic regression analysis adjusting for fast walking and eating habits. RESULTS: Of the 1185 participants, 345 (29.1%) women were equol producers. The proportions of women who had NAFLD (34.8% vs 45.2%) were significantly lower in the equol-producing group than in the non-producing group. Multivariable logistic regression analysis showed that equol production was significantly associated with NAFLD (odds ratio = 0.66, 95% confidence interval: 0.51-0.86). CONCLUSIONS: Equol production was significantly associated with NAFLD in women in their 50s and 60s.

Omega-3 intake is associated with liver disease protection.

Background: Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease are among the most common liver diseases worldwide, and there are currently no Food and Drug Administration (FDA)-approved treatments. Recent studies have focused on lifestyle changes to prevent and treat NAFLD. Omega-3 supplementation is associated with improved outcomes in patients with chronic liver disease. However, it is unclear whether Omega-3 supplementation can prevent the development of liver disease, particularly in individuals at an increased (genetic) risk. Methods: In this UK Biobank cohort study, we established a multivariate cox proportional hazards model for the risk of incident liver disease during an 11 year follow up time. We adjusted the model for diabetes, prevalent cardiovascular disorders, socioeconomic status, diet, alcohol consumption, physical activity, medication intake (insulin, biguanides, statins and aspirin), and baseline characteristics. Results: Omega-3 supplementation reduced the risk of incident liver disease (HR = 0.716; 95% CI: 0.639, 0.802; p = 7.6 × 10-9). This protective association was particularly evident for alcoholic liver disease (HR = 0.559; 95% CI: 0.347, 0.833; p = 4.3 × 10-3), liver failure (HR = 0.548; 95% CI: 0.343, 0.875; p = 1.2 × 10-2), and non-alcoholic liver disease (HR = 0.784; 95% CI: 0.650, 0.944; p = 1.0 × 10-2). Interestingly, we were able to replicate the association with reduced risk of NAFLD in a subset with liver MRIs (HR = 0.846; 95% CI: 0.777, 0.921; p = 1.1 × 10-4). In particular, women benefited from Omega-3 supplementation as well as heterozygous allele carriers of the liver-damaging variant PNPLA3 rs738409. Conclusions: Omega-3 supplementation may reduce the incidence of liver disease. Our study highlights the potential of personalized treatment strategies for individuals at risk of metabolic liver disease. Further evaluation in clinical trials is warranted before Omega-3 can be recommended for the prevention of liver disease.

Essential metal mixtures exposure and NAFLD: A cohort-based case-control study in northern Chinese male adults.

Epidemiologic evidence on metal mixtures and non-alcoholic fatty liver disease (NAFLD) is limited. We aimed to assess the relationship between multiple metal co-exposure and NAFLD among male adults in Northern China. We conducted a cohort-based case-control study with 648 NAFLD and 648 non-NAFLD males. Seven metal concentrations (calcium, copper, iron, magnesium, manganese, selenium, and zinc) were determined in the blood. We used logistic regression and restricted cubic splines (RCS) to estimate the associations between the single metal and NAFLD. The impact of metal mixtures was quantified by the environmental risk score (ERS) in the adaptive elastic-net regression, and the association with NAFLD was estimated by logistic regression. Age-adjusted RCS showed linear relationships between blood calcium, selenium, and NAFLD. Blood copper, iron, magnesium, and manganese were non-linearly associated with NAFLD. Single metal analysis observed significant relationships between calcium, copper, manganese, and NAFLD, with the adjusted odds ratio (95% confidence interval) for quartile 1 vs. quartile 4 of 1.99 (1.30, 3.05), 2.36 (1.52, 3.64), and 1.77 (1.22, 2.55), respectively. However, metal mixtures analysis revealed one squared term (copper [ß = -0.146]) and five metal-metal interactions (calcium × copper [ß = 0.200], copper × magnesium [ß = 0.188], copper × selenium [ß = 0.188], iron × magnesium [ß = 0.143], magnesium × selenium [ß = -0.297]) except the three main effects. Higher ERS indicated a higher risk for NAFLD when exposed to metal mixtures, with an adjusted odds ratio = 6.50 (95% confidence interval: 4.36-9.69) for quartile 4 vs. quartile 1. Mediation analysis suggested that 11.66% of the effect of ERS on NAFLD was suppressed by fasting blood glucose. Our results show that exposure to metal mixtures is associated with a higher risk for NAFLD than the single metal. Interactions between metals suggest the importance of balancing the various metals for health benefits. Prospective cohorts and mechanism studies need to confirm the findings.

The Role of Choline, Soy Isoflavones, and Probiotics as Adjuvant Treatments in the Prevention and Management of NAFLD in Postmenopausal Women.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent condition among postmenopausal women that can lead to severe liver dysfunction and increased mortality. In recent years, research has focused on identifying potential lifestyle dietary interventions that may prevent or treat NAFLD in this population. Due to the complex and multifactorial nature of NAFLD in postmenopausal women, the disease can present as different subtypes, with varying levels of clinical presentation and variable treatment responses. By recognizing the significant heterogeneity of NAFLD in postmenopausal women, it may be possible to identify specific subsets of individuals who may benefit from targeted nutritional interventions. The purpose of this review was to examine the current evidence supporting the role of three specific nutritional factors-choline, soy isoflavones, and probiotics-as potential nutritional adjuvants in the prevention and treatment of NAFLD in postmenopausal women. There is promising evidence supporting the potential benefits of these nutritional factors for NAFLD prevention and treatment, particularly in postmenopausal women, and further research is warranted to confirm their effectiveness in alleviating hepatic steatosis in this population.

Computerized Tomography-Based Screening for Moderate to Severe Hepatic Steatosis in a Multiethnic Population.

Background and Aim Data on prevalence of nonalcoholic fatty liver disease in Hawaii is limited. This study determined the prevalence of moderate to severe hepatic steatosis within a multicultural, multiethnic, and multiracial cohort in Hawaii undergoing computerized tomography (CT) for reasons unrelated to fatty liver disease. Methods The authors performed a retrospective analysis of all patients who were members of an integrated health care system with CT scans including the liver between January 1, 2020, and December 31, 2020. Moderate to severe hepatic steatosis was determined by an average attenuation value < 40 Hounsfield units for non-contrast-enhanced CT and a mean attenuation value < 90 Hounsfield units for contrast-enhanced CT. Patients' electronic medical records were reviewed for existing diagnoses of hepatic steatosis, obesity, and diabetes mellitus type 2 and data to calculate a Fibrosis-4 (FIB-4) index. Results Approximately 26.6% had moderate to severe hepatic steatosis, while only 11.3% of those patients had an active diagnosis of fatty liver disease. Native Hawaiians and Pacific Islanders (33.1%) had the greatest prevalence of hepatic steatosis, followed by White people (28.4%), Asian people (27.7%), and other ethnicities (10.8%). About 61.4% patients with fatty liver had a diagnosis of obesity, while 33.4% had a body mass index < 30.0 kg/m2. Finally, 86.2% patients had enough information in their electronic medical records from which to calculate a FIB-4 score and the mean FIB-4 index was 1.66 ± 3.50. Conclusions Moderate to severe hepatic steatosis is common among patients undergoing CT studies for reasons not related to hepatic steatosis in this multiethnic population most of whom did not have a diagnosis of fatty liver disease.

Dietary selenium intake in relation to non-alcoholic fatty liver disease assessed by fatty liver index and hepatic steatosis index; a cross-sectional study on the baseline data of prospective PERSIAN Kavar cohort study.

BACKGROUND: There is limited and conflicting evidence on the association between selenium and non-alcoholic fatty liver disease (NAFLD). Therefore, the present population-based cross-sectional study aimed to explore the relationship between dietary selenium intake and the risk of NAFLD. METHODS: A total of 3026 subjects from the PERSIAN (Prospective Epidemiological Research Studies in IrAN) Kavar cohort study were included in the analysis. The daily selenium intake was evaluated using a semi-quantitative food frequency questionnaire, and energy-adjusted quintiles of selenium intake (µg/day) were calculated. NAFLD was defined as the fatty liver index (FLI) ≥ 60 or the hepatic steatosis index (HSI) > 36. The association between dietary selenium intake and NAFLD was evaluated using logistic regression analysis. RESULTS: The prevalence rates of NAFLD were 56.4% and 51.9%, based on the FLI and HSI markers, respectively. The odds ratios (ORs) for FLI-defined NAFLD were 1.31 (95% confidence interval (CI): 1.01-1.70) and 1.50 (95% CI: 1.13-1.99) for the fourth and fifth quintiles of selenium intake, respectively, after adjustment for sociodemographic variables, smoking status, alcohol drinking, physical activity, and dietary factors (P trend = 0.002). There was also a similar association between selenium intakes and HSI-defined NAFLD (OR = 1.34 (95% CI: 1.03-1.75) for the fourth quintile and OR = 1.50 (95% CI: 1.12-2.01) for the fifth quintile of selenium intake) (P trend = 0.006). CONCLUSION: In this large sample study, we observed a weak positive association between dietary selenium intake and NAFLD risk.

Non-Alcoholic Fatty Liver Disease and Vitamin D in the UK Biobank: A Two-Sample Bidirectional Mendelian Randomisation Study.

Evidence for a role for vitamin D in non-alcoholic fatty liver disease (NAFLD) pathogenesis is conflicting. As Mendelian randomisation (MR) avoids many limitations of conventional observational studies, this two-sample bidirectional MR analysis was conducted to determine the following: (i) whether genetically predicted 25-hydroxyvitamin D [25(OH)D] levels are a risk factor for NAFLD, and (ii) whether genetic risk for NAFLD influences 25(OH)D levels. Single-nucleotide polymorphisms (SNPs) associated with serum 25(OH)D levels were obtained from the European ancestry-derived SUNLIGHT consortium. SNPs associated with NAFLD or NASH (p-value < 1 × 10-5) were extracted from previous studies and supplemented by genome-wide association studies (GWASs) performed in the UK Biobank. These GWASs were done both without (primary analysis) and with (sensitivity analysis) the population-level exclusion of other liver diseases (e.g., alcoholic liver diseases, toxic liver diseases, viral hepatitis, etc.). Subsequently, MR analyses were performed to obtain effect estimates using inverse variance weighted (IVW) random effect models. Cochran's Q statistic, MR-Egger regression intercept, MR pleiotropy residual sum and outlier (MR-PRESSO) analyses were used to assess pleiotropy. No causal association of genetically predicted serum 25(OH)D (per standard deviation increase) with risk of NAFLD was identified in either the primary analysis: n = 2757 cases, n = 460,161 controls, odds ratio (95% confidence interval): 0.95 (0.76, -1.18), p = 0.614; or the sensitivity analysis. Reciprocally, no causal association was identified between the genetic risk of NAFLD and serum 25(OH)D levels, OR = 1.00 (0.99, 1.02, p = 0.665). In conclusion, this MR analysis found no evidence of an association between serum 25(OH)D levels and NAFLD in a large European cohort.

A proposal from the liver forum for the management of comorbidities in non-alcoholic steatohepatitis therapeutic trials.

The current document has been developed by the Liver Forum who mandated the NAFLD-Associated Comorbidities Working Group - a multistakeholder group comprised of experts from academic medicine, industry and patient associations - to identify aspects of diverse comorbidities frequently associated with non-alcoholic steatohepatitis (NASH) that can interfere with the conduct of therapeutic trials and, in particular, impact efficacy and safety results. The objective of this paper is to propose guidance for the management of relevant comorbidities in both candidates and actual participants in NASH therapeutic trials. We relied on specific guidelines from scientific societies, when available, but adapted them to the particulars of NASH trials with the aim of addressing multiple interacting requirements such as maintaining patient safety, reaching holistic therapeutic objectives, minimising confounding effects on efficacy and safety of investigational agents and allowing for trial completion. We divided the field of action into: first, analysis and stabilisation of the patient's condition before inclusion in the trial and, second, management of comorbidities during trial conduct. For the former, we discussed the concept of acceptable vs. optimal control of comorbidities, defined metabolic and ponderal stability prior to randomisation and weighed the pros and cons of a run-in period. For the latter, we analysed non-hepatological comorbid conditions for changes or acute events possibly occurring during the trial, including changes in alcohol consumption, in order to detail when specific interventions are necessary and how best to manage concomitant drug intake in line with methodological constraints. These recommendations are intended to act as a guide for clinical trialists and are open to further refinement when additional data become available.

Chronic hepatitis B with concurrent metabolic dysfunction-associated fatty liver disease: Challenges and perspectives.

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) has increased among the general population and chronic hepatitis B (CHB) patients worldwide. Although fatty liver disease is a well-known risk factor for adverse liver outcomes like cirrhosis and hepatocellular carcinoma, its interactions with the hepatitis B virus (HBV) and clinical impacts seem complex. The presence of hepatic steatosis may suppress HBV viral activity, potentially leading to attenuated liver injury. In contrast, the associated co-morbidities like diabetes mellitus or obesity may increase the risk of developing adverse liver outcomes. These findings implicate that components of MAFLD may have diverse effects on the clinical manifestations of CHB. To this end, a clinical strategy is proposed for managing patients with concurrent CHB and MAFLD. This review article discusses the updated evidence regarding disease prevalence, interactions between steatosis and HBV, clinical impacts, and management strategies, aiming at optimizing holistic health care in the CHB population.

Dietary patterns and risk of non-alcoholic fatty liver disease in Korean adults: a prospective cohort study.

OBJECTIVES: Dietary patterns can holistically provide insights into the association of food groups and nutrients with the disease. Several studies have evaluated the association of dietary patterns with the risk of non-alcoholic fatty liver disease (NAFLD) in Western populations. However, few studies focused on this topic were conducted on Korean adults. Therefore, in this cohort study, we aimed to investigate the association between dietary patterns and the risk of NAFLD among middle-aged Koreans. DESIGN: The survey was performed at general hospitals and health examination centres in Korea. Dietary intake was assessed using a validated Food Frequency Questionnaire. The dietary patterns were identified using principal component analysis. The HR and 95% CI for NAFLD for each of the quartiles of the three dietary patterns were estimated using a Cox proportional hazards model. SETTING: South Korean Community. PARTICIPANTS: 44 460 healthy Koreans (aged 40-69 years) who completed a follow-up survey from 2012 to 2016 in the Health Examinees study were included. RESULTS: Men and women following a prudent pattern showed a 22% and 36% lower NAFLD risk, respectively (men: HR=0.78; women: HR=0.64). Men and women who highly adhered to the flour-based food and meat pattern had a 29% and 55% higher NAFLD risk, respectively (men: HR=1.29; women: HR=1.55). CONCLUSION: The prudent pattern induced a lower NAFLD risk, whereas the flour-based food and meat pattern induced a higher NAFLD risk. No significant difference was found between the white rice pattern and NAFLD risk.

Nutritional, pharmacological, and environmental programming of NAFLD in early life.

Nonalcoholic fatty liver disease (NAFLD) is the main liver disease worldwide, and its prevalence in children and adolescents has been increasing in the past years. It has been demonstrated that parental exposure to different conditions, both preconceptionally and during pregnancy, can lead to fetal programming of several metabolic diseases, including NAFLD. In this article, we review some of the maternal and paternal conditions that may be involved in early-life programing of adult NAFLD. First, we describe the maternal nutritional factors that have been suggested to increase the risk of NAFLD in the offspring, such as an obesogenic diet, overweight/obesity, and altered lipogenesis. Second, we review the association of certain vitamin supplementation and the use of some drugs during pregnancy, for instance, glucocorticoids, with a higher risk of NAFLD. Furthermore, we discuss the evidence showing that maternal-fetal pathologies, including gestational diabetes mellitus (GDM), insulin resistance (IR), and intrauterine growth restriction (IUGR), as well as the exposure to environmental contaminants, and the impact of microbiome changes, are important factors in early-life programming of NAFLD. Finally, we review how paternal preconceptional conditions, such as exercise and diet (particularly obesogenic diets), may impact fetal growth and liver function. Altogether, the presented evidence supports the hypothesis that both in utero exposure and parental conditions may influence fetal outcomes, including the development of NAFLD in early life and adulthood. The study of these conditions is crucial to better understand the diverse mechanisms involved in NAFLD, as well as for defining new preventive strategies for this disease.

Dietary phytochemical index and the risk of non-alcoholic fatty liver disease: A case-control study among Iranian adults.

BACKGROUNDS: Dietary phytochemical index (DPI) is an inexpensive method for estimating the amounts of phytochemicals in foods. No study has investigated the association between DPI and non-alcoholic fatty liver disease (NAFLD). Our study aimed to compare DPI in patients with NAFLD and the control group. METHODS: This is a case-control study of 250 subjects with NAFLD and 450 healthy subjects attending the Metabolic Liver Disease Research Center as a referral center affiliated to Isfahan University of Medical Sciences. DPI was calculated based on data collected from a 168-item validated food frequency questionnaire. Sociodemographic data, physical activity, and anthropometric measures such as body weight, height, and waist circumference were determined. RESULTS: In the final adjusted model, the odds ratio (OR) of NAFLD across the DPI tertiles decreased significantly (OR = 0.55, 95 %CI = 0.31-0.95) (P-trend = 0.03). The highest vs. lowest tertiles of vegetable and olives PI were significantly associated with a lower risk of NAFLD (OR and 95 % CI = 0.26 (0.14-0.47); OR and 95 % CI = 0.51 (0.29-0.90), p for trend < 0.001, respectively), however, there was no significant relation between other PI components and NAFLD. CONCLUSION: This case-control study suggested that a higher PI score is associated with a reduced chance of NAFLD after adjusting for confounding variables. In addition, the highest tertile of vegetable and olives PI was significantly associated with a lower risk of NAFLD.

Association of Serum Bilirubin With Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Objective: Metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD) are the leading chronic diseases worldwide. There are still many controversies about the association between serum bilirubin and MetS or NAFLD. This study aims to evaluate the association of serum total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL) with MetS and NAFLD. Methods: Multiple databases were searched for relevant studies until November 2021. Randomized controlled trials, cross-sectional and cohort studies evaluating the association between serum bilirubin levels and MetS or NAFLD were included. Results: Twenty-four cross-sectional and cohort studies with 101, 517 participants were finally analyzed. Fifteen studies and 6 studies evaluated the association between bilirubin and MetS or NAFLD in health screening population, respectively, while 3 studies evaluated the association between bilirubin and non-alcoholic steatohepatitis (NASH) in NAFLD patients. Random effect model analysis showed the inverse association between TBIL and MetS in male (95%CI=0.71-0.96) and gender-neutral (95%CI=0.61-0.91) group. However, no significant association was found in females. Notably, the inverse association between DBIL and MetS was noticed in male (95%CI=0.36-0.75), female (95%CI=0.16-0.58) and gender-neutral population (95%CI=0.67-0.92). IBIL level was inversely associated with MetS in females (95%CI=0.52-0.96), whereas no statistical correlation presented in males. TBIL was not statistically correlated with NAFLD in gender-neutral or male subgroup. Similarly, there were no association between DBIL or IBIL and NAFLD in gender-neutral subgroup. However, the negative correlation between DBIL and NAFLD existed in males (95%CI=0.76-0.96). In NAFLD patients, IBIL analysis showed an inverse association with NASH (95%CI=0.01-0.12). Conclusion: Serum TBIL and DBIL levels, especially DBIL levels, assume an inverse correlation with MetS in healthy population. Serum IBIL is inversely associated with the onset and degree of NASH in NAFLD patients. Exogenous bilirubin supplement may be a potential strategy to assist in lowering the risk of developing MetS and NAFLD. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021293349.