Diet, exercise, and supplements: what is their role in the management of the metabolic dysfunction-associated steatotic liver disease in children?

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), is the main cause of chronic liver disease in children and adolescents. Indeed, epidemiological studies have shown that MASLD affects up to 40% of children with obesity. Despite the recent approval of medications that target weight loss in adolescents that could have benefits on pediatric MASLD, lifestyle interventions, such as diet and exercise, remain the mainstay of our therapeutic approach. More specifically, studies on diet alone have focused on the possible role of carbohydrate or fat restriction, albeit without a definite answer on the best approach. Weight loss after dietary intervention in children with obesity and MASLD has a beneficial effect, regardless of the diet used. In relation to the role of exercise in MASLD reversal, indirect evidence comes from studies showing that a sedentary lifestyle leading to poor fitness, and low muscle mass is associated with MASLD. However, research on the direct effect of exercise on MASLD in children is scarce. A combination of diet and exercise seems to be beneficial with several studies showing improvement in surrogate markers of MASLD, such as serum alanine aminotransferase and hepatic fat fraction, the latter evaluated with imaging studies. Several dietary supplements, such as vitamin E, probiotics, and omega-3 fatty acid supplements have also been studied in children and adolescents with MASLD, but with equivocal results. This review aims to critically present available data on the effects of lifestyle interventions, including diet, exercise, and dietary supplements, on pediatric MASLD, thus suggesting a frame for future research that could enhance our knowledge on pediatric MASLD management and optimize clinicians' approach to this vexing medical condition.

Partial validation of a six-month high-fat diet and fructose-glucose drink combination as a mouse model of nonalcoholic fatty liver disease.

PURPOSE: The need to investigate the pathogenesis and treatment of nonalcoholic fatty liver disease (NAFLD) has led to the development of multiple mouse models. The aim of this study was to validate a fast food diet (FFD) mouse model that is introduced as being close to the human disease. METHODS: Eight to nine weeks old male and female C57BL/6 J mice were randomly allocated to a FFD group or to a chow diet (CD) group. Every four weeks, mice were weighed, and blood samples were collected for the measurement of glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TGs) and total cholesterol. After 25 weeks, mice were sacrificed, and liver tissue was histologically evaluated. RESULTS: FFD mice gained more weight (p = 0.049) and presented a higher liver-to-body weight ratio (p < 0.001) compared to CD mice. FFD group presented with greater steatosis, hepatocellular ballooning and NAFLD activity score (NAS), whereas lobular inflammation and fibrosis were not significantly different compared to CD. When stratified by sex, NAS was different between FFD and CD groups in both male and female mice. Group by time interaction was significant for weight, ALT and cholesterol, but not for glucose, AST and TGs. CONCLUSION: FFD mice presented with morphologic and biochemical features of NAFLD and with greater hepatic steatosis, hepatocellular ballooning and NAS, but not lobular inflammation and fibrosis, compared to CD mice. These results only partly validate the FFD mouse model for NAFLD, at least for a 6-month feeding period.

Role of Glucocorticoids in Metabolic Dysfunction-Associated Steatotic Liver Disease.

PURPOSE OF THE REVIEW: To summarize published data on the association between glucocorticoids and metabolic dysfunction-associated steatotic liver disease (MASLD), focusing on the possible pathophysiological links and related treatment considerations. RECENT FINDINGS: Glucocorticoids, commonly used for managing many inflammatory and autoimmune diseases, may contribute to the development and progression of MASLD. Glucocorticoids may induce hyperglycemia and hyperinsulinemia, thus increasing systemic and hepatic insulin resistance, a hallmark of MASLD pathogenesis. Furthermore, glucocorticoids increase adipose tissue lipolysis, and hepatic de novo lipogenesis and decrease hepatic fatty acid ß-oxidation, thus promoting MASLD development. Preclinical evidence also suggests that glucocorticoids may adversely affect hepatic inflammation and fibrosis. 11beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) and 5α-reductase are implicated in the link between glucocorticoids and MASLD, the former enzyme increasing and the latter reducing the glucocorticoid action on the liver. Treatment considerations exist due to the pathogenic link between glucocorticoids and MASLD. Since iatrogenic hypercortisolism is common, glucocorticoids should be used at the minimum daily dose to control the subjective disease. Furthermore, the pharmacologic inhibition of 11ß-HSD1 has provided favorable results in MASLD, both in preclinical studies and early MASH clinical trials. Glucocorticoids are closely linked to MASLD pathophysiology, with specific clinical and therapeutic implications.

Circulating Ferritin in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis.

Objectives: To synthesize data on circulating ferritin between patients with histologically confirmed nonalcoholic fatty liver disease (NAFLD) and non-NAFLD controls. Methods: A systematic literature search was conducted in PubMed, Scopus, and the Cochrane Library. Thirty-one studies comprising data on 5631 individuals (2929 biopsy-proven NAFLD patients and 2702 controls) were included in the meta-analysis. Results: Higher circulating ferritin levels were observed in NAFLD patients than in controls [standardized mean difference (SMD) 1.14; 95% confidence interval (95% CI) 0.73-1.55], in patients with simple nonalcoholic fatty liver (NAFL) than in controls (SMD 0.57; 95% CI 0.34-0.80), in patients with nonalcoholic steatohepatitis (NASH) than in controls (SMD 0.95; 95% CI 0.69-1.22), and in NASH than in NAFL patients (SMD 0.62; 95% CI 0.25-0.99). There was moderate-to-high heterogeneity among studies in the above pairs of comparisons (I2 = 68-97%); no risk of publication bias was observed by Egger's test (P = 0.81, P = 0.72, P = 0.59, P = 0.42, respectively). The heterogeneity was reduced in the subgroup of biopsy-proven controls in all pairs of comparisons (I2 = 0-65%). The heterogeneity was also reduced after excluding studies with the Newcastle-Ottawa Scale (NOS) score <7 (n = 10) for the comparison of NAFLD patients vs. controls (I2 = 54%, P = 0.02). The meta-regression analysis revealed that the male ratio was positively associated with ferritin SMD in the comparison between NAFLD patients and controls and accounted for 32.7% (P = 0.002) of the heterogeneity in this pair of comparison. Conclusions: Circulating ferritin was higher in NAFLD (or NAFL or NASH) patients compared with controls. Higher levels of circulating ferritin were also associated with the severity of the disease, which, however, should be cautiously interpreted.PROSPERO registration ID: CRD42022354025.

Animal studies on glucagon-like peptide-1 receptor agonists and related polyagonists in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent metabolic liver disease closely associated with the epidemics of obesity and type 2 diabetes mellitus (T2DM), but without licensed pharmacological treatment to date. As glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved anti-diabetic and anti-obesity medications, they were also considered a potential therapeutic option for NAFLD. Preclinical studies suggest that GLP-1RAs have a beneficial effect on major NAFLD histological outcomes, i.e., hepatic steatosis and inflammation, through multiple intrahepatic mechanisms, including increased fatty acid ß-oxidation, activation of autophagy, suppression of inflammation, and oxidative stress. Data on hepatic fibrosis are limited or inconclusive, although some studies reported improvement in indices of fibrosis or prevention of fibrosis initiation or reduction of collagen deposition. Whether the positive impact of GLP-1RAs on hepatic histology is indirect, i.e., through their action on extrahepatic tissues, or whether their action is direct, i.e., through activating GLP-1R on the hepatocytes, is still a controversial issue. Alongside GLP-1RAs, newly emerging peptide polyagonists (i.e., synthetic molecules that combine the amino acid sequences of more than one peptide, thus having the ability to bind more than one receptor) are now being investigated in NAFLD with high expectations. This review summarizes the existing knowledge derived from animal studies on the effects of GLP-1RAs and GLP-1RA related peptide polyagonists on NAFLD in an attempt to illuminate areas of uncertainty and provide the groundwork for future animal and clinical research in the field.

Circulating leptin in patients with nonalcoholic fatty liver disease-related liver fibrosis: a systematic review and a meta-analysis.

BACKGROUND AND AIM: Clinical data on the association between leptin levels and nonalcoholic fatty liver disease (NAFLD)-related liver fibrosis are conflicting. This meta-analysis aimed to compare circulating leptin between NAFLD patients with versus without liver fibrosis or non-NAFLD controls. METHODS: A systematic search was conducted in PubMed, Scopus, and the Cochrane Library. Fifteen studies were included, reporting data from 964 individuals (422 NAFLD patients with fibrosis, 297 NAFLD patients without fibrosis, 245 no-NAFLD controls). RESULTS: Leptin standardized mean difference (SMD) was higher in NAFLD patients with fibrosis (F1-F4) than in controls (SMD: 2.27; 95% confidence interval [CI]: 0.81-3.73); however, this association did not remain robust after the exclusion of studies with morbidly obese individuals. No difference was observed in leptin SMD between NAFLD patients with fibrosis and those without fibrosis (F0), and NAFLD patients without fibrosis versus controls. Heterogeneity was high (I2 : 66-98%) among studies. Meta-regression analysis revealed a positive association of leptin SMD with homeostasis model assessment-insulin resistance, when comparing NAFLD patients with fibrosis versus NAFLD patients without fibrosis (beta: 0.53; 95% CI: 0.04-1.03), and a negative association of leptin SMD with age, when comparing NAFLD patients with fibrosis versus controls (beta: -0.29; 95% CI: -0.53 to -0.05). CONCLUSION: Circulating leptin was higher in NAFLD patients with liver fibrosis than non-NAFLD controls, an association, however, attenuated after the exclusion of a study with morbidly obese individuals. Circulating leptin was not different between NAFLD patients with and without fibrosis, or NAFLD patients without fibrosis and controls.

Nonalcoholic fatty liver disease test: an external validation cohort.

PURPOSE: Non-invasive diagnosis of nonalcoholic fatty liver disease (NAFLD) and its advanced phenotypes (e.g., nonalcoholic steatohepatitis; NASH) is a hot research topic. The aim of this report was the validation of a novel non-invasive index of NAFLD, the "NAFLD test," recently introduced for the diagnosis of NAFLD (vs. non-NAFLD controls). METHODS: This was a post-hoc analysis of a previous study. The NAFLD test was calculated in NAFLD patients and non-NAFLD controls; the performance of the test was compared with that of other non-invasive indices of NAFLD (fatty liver index [FLI] and hepatic steatosis index [HSI]), and other indices of NASH (index of NASH [ION] and cytokeratin-18/homeostasis model assessment-insulin resistance/aspartate transaminase index [CHAI]). RESULTS: The NAFLD test was higher in NAFLD patients than in controls (1.89 ± 0.14 vs. 1.30 ± 0.06, respectively; p < 0.001). In NAFLD patients, the NAFLD test was higher in NASH patients than in those with simple nonalcoholic fatty liver (NAFL) (2.21 ± 0.24 vs. 1.57 ± 0.08, respectively; p = 0.007). The area under the receiver operating characteristic curve (AUC) of the NAFLD test was 0.84 (95% CI: 0.74-0.94; p < 0.001) for differentiation between NAFLD and non-NAFLD controls and its performance was similar to that for FLI and HSI. For differentiation between NASH and NAFL patients, the AUC of the NAFLD test was 0.88 (95% CI: 0.62-0.96; p = 0.007) and its performance was superior to that for ION and CHAI. CONCLUSIONS: The NAFLD test was validated in this external cohort for the non-invasive diagnosis of NAFLD patients vs. non-NAFLD individuals. It was also shown to differentiate between NASH and NAFL patients with acceptable accuracy.

The relationship between length of denosumab treatment for postmenopausal osteoporosis and serum TRAcP5b measured six months after the last injection.

To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months after the last injection in postmenopausal women treated for 1-10 years. Serum TRAcP5b values were not related to time of exposure to denosumab. PURPOSE: In women with postmenopausal osteoporosis the aetiology of the observed inverse relationship between duration of denosumab (Dmab) therapy and bone loss after its discontinuation is currently unknown. In studies in mice inhibition of RANKL is associated with an increase in osteomorphs and osteoclast precursors that recycle into osteoclasts and may accumulate with time. We hypothesized that longer inhibition of RANKL by Dmab will be followed by the synchronous formation of a larger number of osteoclasts after stopping treatment. To test this hypothesis, we measured serum TRAcP5b, a marker of osteoclast numbers, in postmenopausal women treated with Dmab for different periods of time up to 10 years. METHODS: TRAcP5b, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at 6.0 months ± 15 days after last Dmab injection in 59 women who had received Dmab for 4.0 ± 2.3 years (range 1-10 years). Of these, 38 were treatment naïve (group 1) and 21 had received other treatments prior Dmab (group 2). RESULTS: Duration of Dmab treatment was not related to serum TRAcP5b values or to TRAcP5b/CTX ratio either in the whole cohort or in each of the two groups separately. In contrast, serum TRAcP5b values were significantly correlated with serum CTX values (rs = 0.619; p < 0.001), but not with serum P1NP values or BMD at all skeletal sites. CONCLUSION: Our observations indicate that serum TRAcP5b, measured at 6 months after a Dmab injection, is not a useful early marker for time-dependent increased accumulation of osteoclasts in humans and for identification of patients at risk for a higher rebound increase in bone resorption.

Tumor Necrosis Factor-Alpha and Adiponectin in Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma.

Nonalcoholic fatty liver disease (NAFLD) is emerging as an important risk factor for hepatocellular carcinoma (HCC), whose prevalence is rising. Although the mechanisms of progression from NAFLD to HCC are not fully elucidated, tumor necrosis factor-α (TNF-α) and adiponectin, as well as their interplay, which seems to be antagonistic, may contribute to the pathophysiology of NAFLD-associated HCC. TNF-α initially aims to protect against hepatocarcinogenesis, but during the progression of NAFLD, TNF-α is increased, thus probably inducing hepatocarcinogenesis in the long-term, when NAFLD is not resolved. On the other hand, adiponectin, which is expected to exert anti-tumorigenic effects, is decreased during the progression of the disease, a trend that may favor hepatocarcinogenesis, but is paradoxically increased at end stage disease, i.e., cirrhosis and HCC. These observations render TNF-α and adiponectin as potentially diagnostic biomarkers and appealing therapeutic targets in the setting of NAFLD-associated HCC, possibly in combination with systematic therapy. In this regard, combination strategy, including immune checkpoint inhibitors (ICIs) with anti-TNF biologics and/or adiponectin analogs or medications that increase endogenous adiponectin, may warrant investigation against NAFLD-associated HCC. This review aims to summarize evidence on the association between TNF-α and adiponectin with NAFLD-associated HCC, based on experimental and clinical studies, and to discuss relevant potential therapeutic considerations.

The role of glucagon-like peptide-1 receptor agonists in nonalcoholic fatty liver disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease, associated with obesity, type 2 diabetes mellitus and dyslipidemia, which can lead to liver cirrhosis and hepatocellular carcinoma in some patients. Apart from lifestyle modifications, which are the cornerstone for its management, several drugs are under evaluation, including glucagon-like peptide-1 receptor agonists (GLP-R1RAs). In this review, we summarized major clinical data concerning the effects of GLP-1RAs on NAFLD, trying to highlight existing knowledge and to elucidate areas of uncertainty, thus providing clues to potential clinical implications and research. AREAS COVERED: Selected clinical studies on GLP-R1As in NAFLD are presented in this narrative review. EXPERT OPINION: There is evidence that treatment with GLP-R1As in NAFLD has beneficial effects on NAFLD, i.e. improvement in liver function tests and histological improvement in hepatic steatosis and inflammation, but not fibrosis. Further research is required toward the early use of GLP-R1Αs, i.e. in NAFLD patients without fibrosis to evaluate whether they may prevent the progression to fibrosis, or in patients with advanced disease in combination with other medications, which may have additive or even synergistic effects on NAFLD.

Potential impact of trained innate immunity on the pathophysiology of metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) occurs in a low-grade inflammatory milieu dependent on highly complex networks that span well-beyond the hepatic tissue injury. Dysfunctional systemic metabolism that characterizes the disease, is further induced in response to environmental cues that modify energy and metabolic cellular demands, thereby altering the availability of specific substrates that profoundly regulate, through epigenetic mechanisms, the phenotypic heterogeneity of immune cells and influence hematopoietic stem cell differentiation fate. This immuno-metabolic signaling drives the initiation of downstream effector pathways and results in the decompensation of hepatic homeostasis that precedes pro-fibrotic events. Recent evidence suggests that innate immune cells reside in different tissues in a memory effector state, a phenomenon termed trained immunity, that may be activated by subsequent exogenous (e.g., microbial, dietary) or endogenous (e.g., metabolic, apoptotic) stmuli. This process leads to long-term modifications in the epigenetic landscape that ultimately precondition the cells towards enhanced transcription of inflammatory mediators that accelerates MAFLD development and/or progression. In this mini review we aimed to present current evidence on the potential impact of trained immunity on the pathophysiology of MAFLD, shedding light on the complex immunobiology of the disease and providing novel potential therapeutic strategies to restrain the burden of the disease.

Similarities and Differences in the Management of Patients with Osteoporotic Vertebral Fractures and Those with Rebound-Associated Vertebral Fractures Following Discontinuation of Denosumab.

Rebound-associated vertebral fractures (RVFx) following denosumab discontinuation are typically multiple, are commonly associated with acute sharp pain, increase the risk of imminent fractures, and are pathogenetically different from common osteoporotic vertebral fractures (VFx). A clinically relevant question is whether patients with RVFx should be managed differently from patients with osteoporotic VFx. To address this question, we performed a systematic search of the PubMed database, and we reviewed current evidence on the optimal management of patients with RVFx. For pain relief of patients with RVFx, potent analgesics, often opioids, are essential. Information on the effectiveness of braces in these patients is scarce. Vertebroplasty and kyphoplasty are strongly contraindicated as they confer a substantial risk for new VFx. Exercise may be helpful, but again evidence is lacking. In contrast to patients with osteoporotic VFx, in whom initial treatment with bone-forming agents is recommended, patients with RVFx should initiate treatment with potent antiresorptives. To summarize, patients who have sustained RVFx following denosumab discontinuation are at a very high risk for new fractures, especially VFx. The management of such patients requires a multidisciplinary approach that should not be restricted to pain relief and administration of antiosteoporotic medication, but should also include back protection, early mobilization, and appropriate exercise.

Lipid Profile after Pharmacologic Discontinuation and Restoration of Menstruation in Women with Endometriosis: A 12-Month Observational Prospective Study.

The lipid profile is affected following menstrual cessation (MC). We aimed to evaluate the effects of goserelin-induced MC and subsequent menstrual restoration (MR) on lipid metabolism. Premenopausal women with histologically verified endometriosis (n = 15) received goserelin monthly for 6 months (6mο), resulting in MC, and were followed-up for another 6 months after MR (12mο). Serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), lipoprotein a ([Lp(a)] and lipidomics were measured at baseline, 6mo and 12mo. Shotgun quantitative deep lipidomics were determined at the level of lipid class category, subclass, species, and fatty acyl chain lengths and degree of saturation. TC (p = 0.006), LDL-C (p = 0.028), HDL-C (p = 0.002), and apoA1 (p = 0.013) increased during goserelin-induced MC and remained practically unchanged during MR. TG, apoB, and Lp(a) did not change. From the deep lipidomics analysis, multivariate statistical analysis demonstrated profound alterations in lipid species with MC, whereas no statistically valid models could be fitted for the restoration period. In conclusion, GnRH-analog-induced MC alters lipid profiles at various levels, from standard blood lipid and lipoprotein profiles to several lipid species as detected by lipidomics analysis. Changes largely persist for at least 6 m after MR.

The Five-Year Effect of a Single Zoledronate Infusion on Bone Mineral Density Following Denosumab Discontinuation in Women with Postmenopausal Osteoporosis.

The long-term effects of zoledronate treatment in women with postmenopausal osteoporosis who stop denosumab therapy when they become osteopenic are not known. In a prospective, randomized, controlled clinical trial we previously reported that a single intravenous infusion of zoledronate 5 mg given to such patients 6 months after the last denosumab injection effectively prevents bone loss in the majority of them for up to 3 years. The study was extended for an additional 2 years and included all 19 patients from one Trial Site of the total 27 patients originally randomized in the zoledronate arm. Baseline characteristics of this cohort treated with denosumab for 2.4 ± 0.2 years were not different from those of the whole initial cohort or from the patients who did not participate in this extension. At the end of 5 years 7 patients had become again osteoporotic requiring additional treatment, 9 remained osteopenic while 3 did not complete the study extension. Thus, more than half of the osteoporotic women who became osteopenic with denosumab treatment and stopped it, maintained the BMD gains 5 years after a single zoledronate infusion with no additional treatment. Whether these results are also applicable to patients treated with denosumab for longer periods remains to be established.

Liver biopsy-based validation, confirmation and comparison of the diagnostic performance of established and novel non-invasive steatotic liver disease indexes: Results from a large multi-center study.

BACKGROUND: Non-invasive tools (NIT) for metabolic-dysfunction associated liver disease (MASLD) screening or diagnosis need to be thoroughly validated using liver biopsies. PURPOSE: To externally validate NITs designed to differentiate the presence or absence of liver steatosis as well as more advanced disease stages, to confirm fully validated indexes (n = 7 NITs), to fully validate partially validated indexes (n = 5 NITs), and to validate for the first time one new index (n = 1 NIT). METHODS: This is a multi-center study from two Gastroenterology-Hepatology Departments (Greece and Australia) and one Bariatric-Metabolic Surgery Department (Italy). Overall, n = 455 serum samples of patients with biopsy-proven MASLD (n = 374, including 237 patients with metabolic-dysfunction associated steatohepatitis (MASH)) and Controls (n = 81) were recruited. A complete validation analysis was performed to differentiate the presence of MASLD vs. Controls, MASH vs. metabolic-dysfunction associated steatotic liver (MASL), histological features of MASH, and fibrosis stages. RESULTS: The index of NASH (ION) demonstrated the highest differentiation ability for the presence of MASLD vs. Controls, with the area under the curve (AUC) being 0.894. For specific histological characterization of MASH, no NIT demonstrated adequate performance, while in the case of specific features of MASH, such as hepatocellular ballooning and lobular inflammation, ION demonstrated the best performance with AUC being close to or above 0.850. For fibrosis (F) classification, the highest AUC was reached by the aspartate aminotransferase to platelet ratio index (APRI) being ~0.850 yet only with the potential to differentiate the severe fibrosis stages (F3, F4) vs. mild or moderate fibrosis (F0-2) with an AUC > 0.900 in patients without T2DM. When we excluded patients with morbid obesity, the differentiation ability of APRI was improved, reaching AUC = 0.802 for differentiating the presence of fibrosis F2-4 vs. F0-1. The recommended by current guidelines index FIB-4 seemed to differentiate adequately between severe (i.e., F3-4) and mild or moderate fibrosis (F0-2) with an AUC = 0.820, yet this was not the case when FIB-4 was used to classify patients with fibrosis F2-4 vs. F0-1. Trying to improve the predictive value of all NITs, using Youden's methodology, to optimize the suggested cut-off points did not materially improve the results. CONCLUSIONS: The validation of currently available NITs using biopsy-proven samples provides new evidence for their ability to differentiate between specific disease stages, histological features, and, most importantly, fibrosis grading. The overall performance of the examined NITs needs to be further improved for applications in the clinic.

Sarcopenia, sarcopenic obesity and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), sarcopenia and sarcopenic obesity (SO) are highly prevalent conditions that may coexist, especially in the aging population, without any approved pharmacologic treatment for all of them. There are multiple pathophysiologic mechanisms suggested to explain an association between NAFLD and sarcopenia or SO, including alterations in the adipokines, cytokines, hepatokines and myokines, which may interplay with other factors, such as aging, diet and physical inactivity. In clinical terms, most observational studies support an association between NAFLD and sarcopenia or SO; importantly, there are few cohort studies indicating higher mortality in patients with NAFLD and sarcopenia. Their association also bears some treatment considerations: for example, pioglitazone or vitamin E, suggested as off label treatment for selected patients with nonalcoholic steatohepatitis, may be recommended in the coexistence of sarcopenia or SO, since limited evidence did not show adverse effects of them on sarcopenia and abdominal obesity. In this review, evidence linking sarcopenia and SO with NAFLD is summarized, with a special focus on clinical data. A synopsis of the major pathophysiological links between NAFLD and sarcopenia/SO is initially presented, followed by selected clinical studies and, finally, treatment considerations in patients with NAFLD and sarcopenia or SO are discussed.