INTRODUCTION — Metabolic dysfunction-associated steatotic liver disease (MASLD; previously termed nonalcohol-associated fatty liver disease [NAFLD]) is a spectrum of disease characterized by hepatic steatosis in the absence of heavy alcohol consumption. MASLD may progress to cirrhosis and is likely an important cause of cryptogenic cirrhosis.
This topic will review the treatment and prognosis of MASLD. The pathogenesis, clinical manifestations, and diagnosis of MASLD are discussed separately. (See "Pathogenesis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease)" and "Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults".)
Several professional societies have published guidelines on the management of MASLD, and our approach is generally consistent with these guidelines [1-3].
SPECTRUM OF DISEASE — MASLD ranges from the more benign condition of metabolic dysfunction-associated steatotic liver (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH; previously termed nonalcoholic steatohepatitis [NASH]), which is at the more severe end of the spectrum. In MASLD, hepatic steatosis is present without evidence of inflammation, whereas in MASH, hepatic steatosis is associated with lobular inflammation and apoptosis that can lead to fibrosis and cirrhosis [4-7]. (See "Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults", section on 'Terminology'.)
The histologic findings and scoring systems used to grade disease activity in patients with MASLD are discussed separately. (See "Histologic scoring systems for chronic liver disease", section on 'Metabolic dysfunction-associated steatotic liver disease (MASLD)'.)
MANAGEMENT
General measures for all patients — The following measures apply to all patients with MASLD:
●Abstain from alcohol – We suggest that patients refrain from alcohol, and in particular, recommend avoiding heavy alcohol use (ie, >14 drinks per week or >4 drinks on a given day for males and >7 drinks per week or >3 drinks on a given day for females) [8]. Heavy alcohol use is associated with disease progression [9]. Whether light to moderate alcohol consumption is harmful is not as clear, and this is discussed below. In the absence of definitive data, we suggest abstinence from alcohol. (See 'Alcohol use' below.)
●Immunizations – Vaccination for hepatitis A virus and hepatitis B virus should be given to patients without serologic evidence of immunity. Additional vaccines for patients with chronic liver disease include pneumococcal vaccination and standard immunizations that are given to the general population (eg, influenza, diphtheria, tetanus boosters) (figure 1 and figure 2). Immunization schedules are described separately. (See "Immunizations for adults with chronic liver disease", section on 'Vaccines in chronic liver disease'.)
●Modify risk factors for cardiovascular disease – Patients with MASLD are at increased risk for cardiovascular disease and often have multiple risk factors for cardiovascular disease (eg, hypertension, dyslipidemia). (See "Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults", section on 'Risk factors and associated conditions'.)
Management of patients with MASLD and diabetes includes optimization of blood glucose control. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and 'Patients with MASH and diabetes' below.)
Most patients with MASLD who have dyslipidemia are candidates for lipid-lowering therapy, which is discussed separately. (See "Statins: Actions, side effects, and administration", section on 'Chronic liver disease' and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)
Weight loss — Weight loss is the primary therapy for most patients with MASLD. We recommend weight loss for all patients with MASLD who are overweight (body mass index [BMI] ≥25 kg/m2) or have obesity (BMI ≥30 kg/m2) because weight loss can lead to improvement in liver biochemical tests, liver histology, serum insulin levels, and quality of life in patients with MASLD [10-13]. We begin with lifestyle interventions including diet modification and exercise. For patients who do not meet weight loss goals after six months, we discuss bariatric surgery. Drug therapy is also an option in certain patients. (See 'Additional treatments' below.)
Initial lifestyle interventions — We advise patients who are overweight or have obesity to lose five to seven percent of body weight at a rate of 0.5 to 1.0 kg per week (1 to 2 lb per week) through lifestyle modifications including dietary therapy and exercise. For patients with suspected or biopsy-proven MASH, the weight loss goal is higher (7 to 10 percent of body weight). We provide dietary counseling for patients and also refer them to a nutritionist. Lifestyle interventions to promote weight loss are discussed separately. (See "Obesity in adults: Overview of management" and "Strength training for health in adults: Terminology, principles, benefits, and risks", section on 'Metabolic dysfunction-associated steatotic liver disease'.)
For some patients, weight loss beyond these initial targets may be required. If the serum alanine aminotransferase (ALT) level does not normalize (ALT <20 for females and <30 for males) after achieving the weight loss goal, we advise patients to lose additional weight. (See 'Laboratory monitoring' below.)
For patients with MASH or advanced fibrosis who do not meet their weight loss goals after six months of lifestyle interventions, we discuss additional options, including bariatric surgery, which is presented below. (See 'Bariatric surgery' below.)
Several studies suggest that weight loss of at least 5 percent of body weight is necessary to improve hepatic steatosis, although the long-term benefits of such weight loss are unknown. In a meta-analysis of eight trials including 373 patients, losing ≥5 percent of body weight resulted in improvement in hepatic steatosis, while losing of ≥7 percent of body weight was associated with improvement in liver inflammation and grade of disease activity [14].
In another trial including 31 patients with BMI ranging from 25 to 40 kg/m2 who had biopsy-proven MASH, enrollment in a weight loss and exercise program resulted in greater weight loss after one year compared with a structured education program (9 versus 0.2 percent of body weight) [11]. Patients in the weight loss and exercise group had higher rates of histologic improvement compared with the education group (72 versus 30 percent).
Increasing physical activity has been linked to a survival benefit for patients with MASLD [15,16]. In a longitudinal study of the National Health and Nutrition Examination Survey including 2793 individuals with MASLD, longer duration of physical activity (measured by accelerometers) was associated with lower risk of all-cause mortality during an average follow-up of nearly 11 years (highest quartile of activity compared with lowest quartile: adjusted hazard ratio [aHR] 0.46, 95% CI 0.28-0.75) [16]. In addition, duration of physical activity was associated with lower risk of cardiovascular disease-related mortality (highest quartile of activity compared with lowest quartile: aHR 0.28, 95% CI 0.08-0.98).
Additional treatments
Bariatric surgery — We refer patients with MASH or advanced fibrosis (but without decompensated cirrhosis) for bariatric surgery if they do not meet their weight loss goals after six months of lifestyle interventions, including two visits for nutritional counseling. Bariatric surgery is a promising approach for patients with MASLD, and histologic improvement has been observed postoperatively [17-28]. However, worsening fibrosis occurs in some patients following bariatric surgery, and all patients should have their liver biochemical tests monitored postoperatively (eg, at six weeks, three months, and six months after surgery). We also monitor patients with cirrhosis at one month and three months postoperatively for signs of decompensated cirrhosis (eg, ascites, hepatic encephalopathy), which can occur as a result of surgery. (See "Outcomes of bariatric surgery", section on 'Nonalcoholic fatty liver disease'.)
Drug therapy — Pharmacologic therapy can be used to promote weight loss in patients who fail to achieve their goals through diet and exercise alone. Recommendations for the use of drug therapy to promote weight loss vary greatly among clinicians. Some UpToDate contributors do not use drug therapy often, whereas others prescribe medications in selected patients after providing extensive counseling about lifestyle measures.
We may use a GLP-1 receptor agonist (off-label) for patients with biopsy-proven MASH with fibrosis stage ≥F2 who do not achieve weight loss with lifestyle interventions. We typically begin a GLP-1 receptor agonist (eg, semaglutide, liraglutide) with the same dosing that is used for the labeled indication (obesity) (table 1). We titrate the dose to achieve a weight loss goal of 7 to 10 percent of body weight. For such patients, we also continue to promote lifestyle interventions as long-term therapy. (See 'Initial lifestyle interventions' above.)
Drug therapies for weight loss including administration, dosing, and adverse effects are discussed in more detail separately. (See "Obesity in adults: Drug therapy".)
Pharmacologic therapies — Options for pharmacologic, liver-targeted therapy for MASLD are expanding (eg, vitamin E, some insulin sensitizers, a thyroid hormone receptor-beta agonist). However, we do not use them in all patients. We usually reserve pharmacologic therapy for patients who do not achieve their weight loss goals and have biopsy-proven MASH with fibrosis stage ≥2. The approach also depends on whether the patient has diabetes mellitus.
Pharmacologic therapies have been studied for the treatment of patients with MASH. However, most trials have been too short to determine an impact on important patient-centered clinical outcomes (eg, decompensated cirrhosis) and instead report on surrogate outcomes, such as serum aminotransferases or histologic findings [29].
We anticipate using resmetirom, a thyroid hormone receptor-beta agonist, for patients with MASH and fibrosis stage F2 or F3 (table 2) who do not achieve sustained weight loss [30-32]. Additional studies will help inform the role of resmetirom in clinical practice. Patients with cirrhosis were excluded from published clinical trials, but ongoing trials are evaluating safety and efficacy of resmetirom in such patients.
Dosing for resmetirom is based on body weight [30]:
●<100 kg: 80 mg by mouth once daily
●≥100 kg: 100 mg by mouth once daily
Prior to prescribing resmetirom, clinicians should review the patient's prescribed medications, over-the-counter medications, and dietary supplements and use a tool such as the UpToDate drug interactions program to assess specific drug interactions and potential ways to mitigate them. Resmetirom should not be used with OATP 1B1, IB3 inhibitors (eg, cyclosporine) or strong CYP2C8 inhibitors (eg, gemfibrozil) [30].
Data from clinical trials suggested that resmetirom improved MASH and stage of liver fibrosis. In a trial comparing resmetirom (80 or 100 mg) with placebo in 966 adults with biopsy-confirmed MASH and a liver fibrosis stage of F1B, F2, or F3, resmetirom resulted in higher rates of MASH resolution at 52 weeks (25.9 and 29.9 percent respectively versus 9.7 percent) [32]. In addition, resmetirom resulted in higher rates of improving fibrosis by at least one stage (24.2 and 25.9 percent respectively versus 14.2 percent). Diarrhea and nausea were reported more frequently in the treatment groups.
Patients with MASH but without diabetes — For patients with biopsy-proven MASH and fibrosis stage ≥2 who do not have diabetes mellitus, we generally suggest vitamin E, at a dose of 800 international units daily. Some studies suggest that vitamin E improves steatosis and inflammation in such patients. However, because data are mixed and there are potential safety concerns with high-dose vitamin E, we discuss the potential risks and benefits of vitamin E therapy and individualize the decision based on patient preference.
Since the studies showing a benefit of vitamin E did not include patients with diabetes mellitus or decompensated cirrhosis, we do not use vitamin E in such patients. This is consistent with recommendations from the American Association for the Study of Liver Diseases (AASLD) [1].
We do not use pioglitazone for patients with MASH but without diabetes mellitus because of its potential adverse effects as discussed below. (See 'Patients with MASH and diabetes' below.)
Some, but not all, randomized trials support the use of vitamin E for MASH, but the conflicting findings may be related to differences in trial design [33-40]. A meta-analysis that included five trials found no histologic benefits with vitamin E, though there was significant heterogeneity among the studies with respect to the formulation of vitamin E used, the patient population, the duration of treatment, and the addition of lifestyle modifications [29].
However, the largest randomized trial included in the meta-analysis (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with MASH) did suggest a benefit with vitamin E. The trial included 247 adults with MASH without diabetes who were randomly assigned to pioglitazone (30 mg daily), vitamin E (800 international units daily), or placebo for 96 weeks [35]. Patients treated with vitamin E were more likely to have improvement in their global histology score compared with patients who received placebo (43 versus 19 percent). A subsequent report from the trial found that improvement in ALT was more common in patients receiving vitamin E compared with placebo (48 versus 16 percent) [41]. This is consistent with observational studies that suggested improvement in aminotransferase levels in patients with MASH who received vitamin E [42]. The potential benefit is thought to be related to its antioxidant properties. (See "Overview of vitamin E".)
High-dose vitamin E supplementation (≥400 international units per day) has been inconsistently associated with an increase in all-cause mortality. Underlying comorbidities or use of other supplements in patients using higher doses may have confounded the results, making their interpretation uncertain. Therefore, we feel that vitamin E is a reasonable intervention for patients with MASH and fibrosis stage ≥2 who do not have diabetes mellitus. (See "Vitamin intake and disease prevention", section on 'All-cause mortality'.)
We avoid vitamin E in male patients with either a personal history or strong family history of prostate cancer. The association of vitamin E supplementation with the risk of prostate cancer is discussed separately. (See "Chemoprevention strategies in prostate cancer", section on 'Vitamin E'.)
Patients with MASH and diabetes — For patients with diabetes mellitus, the presence of MASH can inform the choice of glucose lowering therapy in some cases. Although initial therapy for type 2 diabetes mellitus is typically with metformin, which does not improve liver histology [43,44], the beneficial impact on liver histology with certain other insulin-sensitizing agents could be a consideration when choosing a second-line agent for patients with MASH who cannot take metformin or need additional glucose-lowering therapy. In this setting, pioglitazone and glucagon-like peptide-1 (GLP-1) receptor agonists are reasonable options.
In patients with diabetes mellitus and biopsy-proven MASH, pioglitazone improves fibrosis as well as inflammation and steatosis. GLP-1 receptor agonists also appear to provide some benefits for patients with MASH. The potential benefits of these drugs must be balanced with their associated adverse effects. For example, use of pioglitazone is limited because it is associated with increased risk of weight gain, heart failure, and fractures. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Monotherapy failure' and "Thiazolidinediones in the treatment of type 2 diabetes mellitus" and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Adverse effects'.)
The overall approach to management of blood glucose in type 2 diabetes is discussed elsewhere. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".)
Several trials have demonstrated the impact of these agents in patients with MASH:
●Pioglitazone – Thiazolidinediones, and specifically pioglitazone, improve liver biochemical and histologic parameters in patients with MASH [33,35,45-51]. The effect of thiazolidinediones on histologic parameters in MASH was examined in a meta-analysis of four trials that compared thiazolidinediones with placebo in 334 patients with MASH [52]. The analysis found that compared with placebo, thiazolidinediones were more likely to improve hepatic histologic parameters such as ballooning degeneration (OR 2.1, 95% CI 1.3-3.4), lobular inflammation (OR 2.6, 95% CI 1.7-4.0), and steatosis (OR 3.4, 95% CI 2.2-5.3). Improvement in fibrosis was not seen when all thiazolidinediones were examined, but when the analysis was limited to three studies that used pioglitazone, there was a significant improvement in fibrosis among patients treated with pioglitazone compared with placebo (OR 1.7, 95% CI 1.0-2.8).
It is likely that long-term treatment is required to achieve a clinically important benefit because the improvements seen with pioglitazone may reverse if the drug is stopped [45].
●GLP-1 receptor agonists [53-55]:
•Liraglutide – In a trial including 52 patients with MASH who were assigned to receive liraglutide or placebo for 48 weeks, an end-of-treatment biopsy was performed in 23 patients in the liraglutide arm and in 22 patients in the placebo arm [53]. MASH resolved in nine patients (39 percent) who received liraglutide, and in two patients (9 percent) who received placebo (RR 4.3; 95% CI 1.0-17). With regard to fibrosis progression, patients who received liraglutide were less likely to have progression of fibrosis (9 versus 36 percent; RR 0.2; 95% CI 0.1-1.0).
•Semaglutide – In a phase 2 trial including 320 patients with biopsy-proven MASH and liver fibrosis of stage F1, F2 or F3, semaglutide (0.4 mg once daily) resulted in higher rates of histologic resolution of MASH compared with placebo after 72 weeks (59 versus 17 percent; OR 6.87, 95% CI 2.60-17.63) [55]. Lower doses of semaglutide (0.1 mg or 0.2 mg once daily) were less effective but were also more likely to result in histologic resolution compared with placebo (40 percent; OR 3.36, 95% CI 1.29-8.86, and 36 percent; OR 2.71, 95% CI 1.06-7.56, respectively). However, rates of improvement in liver fibrosis stage were not significantly different between the treatment groups and placebo. Gastrointestinal side effects (eg, nausea, vomiting) were more frequently reported with semaglutide compared with placebo, although statistical analysis was not provided. Additional data on histologic outcomes and side effects are needed before semaglutide is used routinely for patients with MASH in the absence of other indications (eg, type 2 diabetes mellitus). (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Adverse effects'.)
The apparent benefit of certain insulin-sensitizing agents for MASLD is likely related to the role insulin resistance plays in the development of MASLD. (See "Pathogenesis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease)", section on 'Insulin resistance'.)
We do not use vitamin E in patients with diabetes because studies showing a benefit from vitamin E did not include these patients [35,41].
Therapies with uncertain benefit — Other medical therapies have been examined for the treatment of MASLD, but none has been studied sufficiently to recommend its use as treatment for fatty liver or MASH:
●Atorvastatin – Pilot studies found a benefit from atorvastatin on aminotransferase levels in patients with MASLD [56,57]. The use of atorvastatin was then examined in a secondary analysis of a trial looking at the effect of atorvastatin, vitamin C, and vitamin E on the development of cardiovascular events in healthy adults [58]. Two of the exclusion criteria for the study were diabetes and serum aminotransferases >1.5 times the upper limit of normal. At baseline, 80 patients had MASLD based upon imaging criteria. After a mean of 3.6 years of follow-up, fewer patients in the treatment arm still had MASLD compared with the placebo arm (34 versus 70 percent; adjusted OR 0.36, 95% CI 0.16-0.83).
However, the conclusions that can be drawn from the trial are limited because patients did not receive atorvastatin alone, only in combination with vitamin E and C, because the diagnosis of MASLD was based upon imaging criteria and not histology, and because the exclusion criteria (diabetes or elevated aminotransferases) limit its generalizability.
●Omega-3 fatty acids – Studies have suggested a benefit of omega-3 fatty acids in patients with MASLD [59,60]. In a meta-analysis of nine studies with 355 patients, treatment with omega-3 fatty acids was associated with improvement in hepatic steatosis as well as aspartate aminotransferase levels [60]. There was also a trend toward improvement in alanine aminotransferase levels. When the analysis was restricted to data from randomized trials, only hepatic steatosis continued to show improvement with omega-3 fatty acid treatment [60-63].
●Aspirin – Limited data suggest that daily aspirin use is beneficial for patients with MASLD [64-66]. In the enrollment phase of a prospective cohort study including 361 patients with biopsy-proven MASLD, daily aspirin users were less likely to have MASH (adjusted odds ratio [aOR] 0.68, 95% CI 0.37-0.89) and fibrosis (aOR 0.54, 95% CI 0.31-0.82) compared with daily aspirin nonusers [64]. In addition, among 317 patients without advanced fibrosis at baseline, daily aspirin users were less likely to progress to advanced fibrosis compared with nonusers (adjusted hazard ratio 0.63, 95% CI 0.43-0.85) during 3692 person-years of follow-up. These results are promising, and future trials may add to data supporting the hepatoprotective effects of aspirin.
Laboratory monitoring — We obtain serum aminotransferases (ALT and aspartate aminotransferase) every three to six months after patients implement lifestyle interventions to achieve and maintain their weight loss goals. If the aminotransferases do not return to normal levels with weight loss or if they increase, we evaluate the patient for an alternative cause of liver disease. The evaluation of patients with abnormal liver biochemical tests is discussed separately. (See "Approach to the patient with abnormal liver tests".)
Monitoring for fibrosis — Our approach to monitoring patients for advanced fibrosis depends on whether they have biopsy-proven MASH and if they achieved weight loss goals and normalization of serum aminotransferases:
●Patients with biopsy-proven MASH – For patients with biopsy-proven MASH, we obtain a noninvasive assessment for advanced fibrosis at a time interval determined by their clinical course:
•For patients who have not been able to lose at least five to seven percent of their body weight and/or have elevated serum aminotransferases, we obtain noninvasive assessment every three years.
•For patients who achieve their weight loss goals and have normal serum aminotransferases, we obtain noninvasive assessment every four years.
If the noninvasive assessment shows a low-risk fibrosis score (≤F1), we continue monitoring patients every four years (if weight loss was achieved and maintained) or every three years (if weight loss was not achieved or maintained). Patients with MASH and no fibrosis or minimal fibrosis have an excellent prognosis and thus, close follow-up is not needed [67].
If the noninvasive assessment shows an increased, high-risk fibrosis score (≥F2), we discuss obtaining a follow-up liver biopsy with the patient to evaluate for advanced fibrosis. If the biopsy does not show cirrhosis, we continue to monitor the patient with noninvasive imaging at intervals as described above. If the liver biopsy shows cirrhosis, further management includes preventing and identifying complications of cirrhosis (eg, variceal hemorrhage, hepatocellular carcinoma), and this is discussed separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)
●Patients without biopsy proven MASH – We do not routinely obtain a noninvasive assessment for fibrosis in patients with MASLD but without biopsy-proven MASH. If the patient’s clinical status subsequently changes (eg, additional weight gain, development of other features of metabolic syndrome), we obtain a noninvasive assessment of fibrosis every three to four years. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Definition'.)
The method of noninvasive evaluation depends on the availability, and options include elastography (eg, vibration-controlled transient elastography, magnetic resonance elastography) and serum fibrosis markers. (See "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography" and "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations", section on 'Imaging examinations'.)
We monitor patients with vibration-controlled transient elastography (VCTE), a noninvasive, point-of-care tool that can exclude advanced fibrosis based on liver stiffness measurements [68]. In a prospective study of 120 patients with biopsy-proven MASLD, VCTE correctly identified 74 patients (45 percent) as having low risk for advanced fibrosis. This approach would avoid the need for liver biopsy in these low-risk patients while those at high risk for fibrosis generally require confirmatory biopsy or further imaging.
SPECIAL POPULATIONS
Patients with cirrhosis — The management of cirrhosis due to MASLD is similar to that for cirrhosis due to other causes and includes management of portal hypertension, screening for hepatocellular carcinoma, and evaluation for liver transplantation for patients with decompensated cirrhosis. The approach to managing patients with cirrhosis is presented elsewhere. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis" and "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)
DISEASE COURSE
Advanced fibrosis — Patients with MASLD are at risk for advanced fibrosis, defined histologically as stage F2 or higher (table 2). Cirrhosis develops when simple steatosis progresses to steatohepatitis and then to fibrosis. The fibrosis stage is the only measure that correlates with outcomes such as liver-related illness, liver transplantation and liver-related mortality in patients with MASLD [67,69,70]. (See 'Monitoring for fibrosis' above.)
While the risk of disease progression among patients with MASLD has been evaluated in multiple studies, the results have been variable, and the risk of developing advanced fibrosis among patients with MASLD is unclear [4-7,71-79]. A meta-analysis that included 11 studies looked at progression to fibrosis in 366 patients with MASLD [80]. Overall, the fibrosis stage progressed in 132 patients (36 percent), remained stable in 158 patients (46 percent), and improved in 76 patients (21 percent). It appears that patients with simple steatosis on biopsy are at lower risk for developing advanced fibrosis, whereas those with steatohepatitis are at higher risk [81]. In addition, some patients with fibrosis show regression of their disease [71-73].
In a cohort study of 129 patients with MASLD who had two follow-up biopsies in addition to clinical and biochemical evaluations, 12 patients (9 percent) developed symptoms of end-stage liver disease in mean follow-up time of 19.8 years [6]. In 113 patients with baseline low fibrosis (defined as stage <F3), 18 patients (16 percent) developed advanced fibrosis (F3 or F4) by the end of the study period. (See "Histologic scoring systems for chronic liver disease", section on 'Metabolic dysfunction-associated steatotic liver disease (MASLD)'.)
Risk factors — Factors that have been associated with advanced fibrosis can be classified as patient- or disease-related:
●Patient-related risk factors:
•Alcohol use (see 'Alcohol use' below).
•Body mass index ≥28 kg/m2 [82,83].
•Diabetes mellitus [69,84].
•Older age (eg, ≥50 years) [73,85].
●Disease-related risk factors
•Histologic evidence of inflammation on liver biopsy (see 'Hepatic inflammation' below).
•Ballooning degeneration plus Mallory hyaline or fibrosis on biopsy [69].
•Elevated serum aminotransferases (eg, ≥2 times the upper limit of normal) [82,84-86].
Coffee consumption has been associated with a lower risk of progressing to fibrosis [87].
Several statistical models have been described to predict fibrosis, but none have been extensively validated [82,86,88-90].
Alcohol use — We suggest that patients refrain from alcohol, and in particular, we recommend avoiding heavy alcohol use (ie, >14 drinks per week or >4 drinks on a given day for males and >7 drinks per week or >3 drinks on a given day for females) [8]. (See 'General measures for all patients' above.)
Heavy alcohol use among patients with MASLD has been associated with hepatic steatosis, hepatic injury, and fibrosis progression [9]. In a study of 71 patients with MASLD followed for a mean of 14 years, 17 patients (24 percent) had fibrosis progression [9]. Heavy episodic drinking (defined in this study as more than 60 grams of alcohol on one occasion for males or 48 grams for females) was more common in those with fibrosis progression than in those without progression (47 versus 11 percent).
We also suggest that patients with MASLD abstain from consuming any alcohol. The effect of light or moderate alcohol consumption on disease progression is less clear because data provide mixed results and prospective studies are limited. Some studies suggest that the consumption of as little as two drinks per day in those who are overweight (and one drink per day in those with obesity) is associated in hepatic injury [91-93]. In a cohort study of 285 patients with MASLD, modest alcohol use, compared to no alcohol use, was also associated with less improvement in steatosis and level of aspartate transaminase as well as decreased chance of MASH resolution. In addition, moderate alcohol consumption does not appear to lower the risk of cardiovascular disease for patients with MASLD, in contrast to the general population [94]. (See "Cardiovascular benefits and risks of moderate alcohol consumption".)
However, other data suggest that light or moderate alcohol consumption may have beneficial effects on the liver [95,96]. This was seen in a cross-sectional study that compared 251 lifetime nondrinkers with MASLD with 331 modest drinkers with MASLD [95]. Modest drinkers had lower odds for fibrosis (OR 0.56; 95% CI 0.41-0.77) and ballooning hepatocellular injury (OR 0.66; 95% CI 0.48-0.92) compared with nondrinkers.
Hepatic inflammation — Histologic evidence of hepatic inflammation is an important risk factor for developing advanced fibrosis. In a systematic review that included 187 patients with paired biopsies, the median time to develop advanced fibrosis among those with inflammation on the initial biopsy was 4.2 years, compared with 13.4 years for those without inflammation [73]. After adjusting for potential confounders, the presence of any inflammation on the initial biopsy increased the chance of progressing to advanced fibrosis 2.5-fold compared with patients who did not have inflammation.
Hepatocellular carcinoma — Surveillance for hepatocellular carcinoma (HCC) is recommended for patients with MASH-related cirrhosis. Routine surveillance intervals, imaging tests, and management of imaging results are discussed separately. (See "Surveillance for hepatocellular carcinoma in adults".)
We do not obtain surveillance imaging for patients without cirrhosis, because the risk of HCC-related mortality is low in the absence of cirrhosis.
Patients with cirrhosis due to MASLD are at higher risk for HCC compared with patients without cirrhosis [97,98]. In a systematic review of 61 studies and case series of patients with MASLD or MASH, the risk of HCC among those with cirrhosis ranged from 2.4 percent over seven years to 12.8 percent over three years [97]. Among those without cirrhosis, the risk of mortality from HCC was 0 to 3 percent after follow-up periods of up to 20 years.
It has been shown across different care settings that patients with MASH-related cirrhosis have lower rates of HCC surveillance compared with patients with cirrhosis from other etiologies such as hepatitis C virus infection [99-101].
Mortality — Whether patients with MASLD have increased overall mortality rates compared with the general population is not clear. While small population-based studies have suggested a mortality risk [70,102,103], the largest study from the United States suggests that the overall mortality rate is not increased in the absence of fibrosis. The National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2012 included 6000 adults in whom rates of MASLD and advanced fibrosis, as determined by the MASLD activity score, were 30 and 10.3 percent, respectively [104]. Compared with individuals without MASLD, overall mortality was lower in MASLD participants without fibrosis (HR 0.41, 95% CI 0.22-0.76), while mortality was higher in MASLD participants with advanced fibrosis (HR 3.13, 95% CI 1.93-5.08).
Fibrosis stage has been associated with risk of mortality. In a study including 1773 adults with MASLD who were followed for a median of four years, the risk of all-cause mortality was higher for patients with stage F4 fibrosis (cirrhosis, HR 3.9) and stage F3 fibrosis (bridging fibrosis, HR 1.9) compared with F0 to F2 fibrosis (1.76 and 0.89 deaths per 100 person-years, respectively, versus 0.32 deaths per 100 person-years) [105]. The risk of liver-related mortality was higher for patients with stage F4 fibrosis (HR 12.7) and stage F3 fibrosis (HR 5.8) compared with F0 to F2 fibrosis (0.68 and 0.28 deaths per 100 person-years, respectively, versus 0.04 deaths per 100 person-years). These data underscore the importance of preventing disease progression in patients without advanced fibrosis or cirrhosis and the impact of achieving regression in patients with advanced disease.
Cardiovascular disease is the most common cause of death among patients with MASLD. A previous study (NHANES III), which showed similar trends in mortality, found that the increase in mortality in MASLD patients with fibrosis (as measured by the MASLD fibrosis score) was due almost exclusively to cardiovascular causes (HR 3.46, 95% CI 1.91-6.25) [106]. Risk factors for cardiovascular disease (eg, diabetes, hyperlipidemia) can be identified and managed in patients with MASLD. (See 'General measures for all patients' above.)
Patients with MASH are at increased risk for liver-related death compared with patients with fatty liver but without MASH [70,102,107,108].
Liver decompensation — Fibrosis stage has been associated with risk of liver decompensation. In a study including 1773 adults with MASLD who were followed for a median of four years, the risk of new onset hepatic decompensation was higher for patients with stage F4 fibrosis (cirrhosis) and stage F3 fibrosis (bridging fibrosis) compared with F0 to F2 fibrosis (2.69 and 0.99 events per 100 person-years, respectively, versus 0.05 events per 100 person-years) [105].
WHEN TO REFER — Referral to a hepatologist is indicated for patients with MASLD and any of the following features (see 'Monitoring for fibrosis' above and "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Clinical manifestations'):
●Aminotransferases (alanine aminotransferase and aspartate aminotransferase) that remain elevated despite loss of ≥5 percent of body weight (to evaluate for other etiologies of liver disease)
●Clinical features of advanced liver disease (eg, ascites, splenomegaly, jaundice)
●Steatohepatitis on liver biopsy
●Advanced fibrosis (fibrosis stage ≥F3) on a noninvasive liver assessment
Patients who develop cirrhosis and have complications (eg, ascites, variceal bleeding) or a model for end-stage liver disease (MELD) score ≥10 (MELDNa score) should be referred for a liver transplantation evaluation. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease)".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Metabolic dysfunction-associated steatotic liver disease (The Basics)").
●Beyond the Basics topics (see "Patient education: Metabolic dysfunction-associated steatotic liver disease (Beyond the Basics)").
SUMMARY AND RECOMMENDATIONS
●General measures – The following general measures apply to patients with metabolic dysfunction-associated steatotic liver disease (MASLD) (see 'General measures for all patients' above):
•For patients without serologic evidence of immunity, vaccination for hepatitis A virus and hepatitis B virus.
•Standard, age-appropriate immunizations (figure 1 and figure 2).
•For patients with hyperlipidemia, lipid-lowering therapy. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)
•For patients with diabetes, optimizing blood glucose control. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)
●Weight management – We recommend weight loss for patients with obesity (Grade 1B). Weight loss has been associated with histologic improvement in patients with MASLD. We advise patients to lose a minimum of five to seven percent of body weight at a rate of 0.5 to 1.0 kg per week (1 to 2 lb per week) through lifestyle modifications, including dietary therapy and exercise. (See 'Weight loss' above and "Obesity in adults: Overview of management".)
●Avoiding alcohol – For patients with MASLD, we recommend refraining from heavy alcohol consumption (Grade 1A) and suggest abstinence from alcohol (Grade 2C). Heavy alcohol use is associated with alcohol-related liver disease and other adverse consequences, including cancers of the mouth and esophagus. In patients with or at risk for MASLD, heavy alcohol use is associated with hepatic steatosis, hepatic injury, and fibrosis progression. Whether light to moderate alcohol consumption is harmful remains somewhat uncertain as data are mixed. In the absence of definitive data, we suggest abstinence from alcohol for patients with MASLD. (See 'General measures for all patients' above and 'Alcohol use' above and "Risky drinking and alcohol use disorder: Epidemiology, clinical features, adverse consequences, screening, and assessment".)
●Medical therapy
•Patients with MASH but without diabetes mellitus – For patients with biopsy-proven steatohepatitis (MASH) and fibrosis stage ≥2 but without diabetes, we suggest using vitamin E (800 international units per day) (Grade 2C). Limited evidence supports a benefit of vitamin E in patients without diabetes, but some observational studies suggest a possible increase in all-cause mortality with higher dose vitamin E. As a result, we discuss the risks and benefits with the patient before starting treatment. (See 'Patients with MASH but without diabetes' above.)
•Patients with MASH and diabetes mellitus – For patients with MASH and diabetes mellitus, the presence of MASH can inform the choice of glucose-lowering therapy. Although initial therapy for type 2 diabetes mellitus is typically with metformin, the beneficial impact on liver histology with certain other insulin-sensitizing agents could be a consideration when choosing a second-line agent for patients with MASH who cannot take metformin or need additional glucose-lowering therapy. In this setting, pioglitazone and GLP-1 receptor agonists (eg, liraglutide, semaglutide) are reasonable options. (See 'Patients with MASH and diabetes' above and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Monotherapy failure'.)
●Laboratory monitoring – We obtain serum aminotransferases (alanine aminotransferase and aspartate aminotransferase) three and six months after patients with MASLD implement lifestyle interventions for weight loss. If the aminotransferases do not return to normal levels with weight loss or if they increase, we evaluate for an alternative cause of liver disease. (See 'Laboratory monitoring' above and "Approach to the patient with abnormal liver tests".)
●Monitoring for fibrosis – For patients with biopsy-proven MASH, we obtain a noninvasive assessment for advanced fibrosis at a time interval determined by their clinical course (see 'Monitoring for fibrosis' above):
•For patients who have not been able to lose at least five to seven percent of their body weight and/or have elevated serum aminotransferases, we obtain a noninvasive assessment every three years.
•For patients who achieve their weight loss goals and have normal serum aminotransferases, we obtain a noninvasive assessment every four years.
ACKNOWLEDGMENT — The UpToDate editorial staff thank Dr. Sunil Sheth for his contributions as author to prior versions of this topic review.
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