INTRODUCTION — Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disease characterized by hepatic steatosis in the absence of excessive alcohol consumption. NAFLD may progress to cirrhosis and is likely an important cause of cryptogenic cirrhosis [1,2].
This topic will review the treatment and prognosis of NAFLD. The pathogenesis, clinical manifestations, and diagnosis of NAFLD are discussed separately. (See "Pathogenesis of nonalcoholic fatty liver disease" and "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)
SPECTRUM OF DISEASE — NAFLD ranges from the more benign condition of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), which is at the more severe end of the spectrum. In NAFL, hepatic steatosis is present without evidence of inflammation, whereas in NASH, hepatic steatosis is associated with lobular inflammation and apoptosis that can lead to fibrosis and cirrhosis [1-4]. The histologic findings and scoring systems used to grade disease activity in patients with NAFLD are discussed separately. (See "Histologic scoring systems for chronic liver disease", section on 'Nonalcoholic fatty liver disease' and "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Histologic findings'.)
MANAGEMENT
General measures for all patients — The following measures apply to all patients with NAFLD:
●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 men and >7 drinks per week or >3 drinks on a given day for women) [5]. Heavy alcohol use is associated with disease progression [6]. 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 patients with chronic liver disease", section on 'Vaccines in chronic liver disease'.)
●Modify risk factors for cardiovascular disease – Patients with NAFLD are at increased risk for cardiovascular disease and often have multiple risk factors for cardiovascular disease (eg, hypertension, hyperlipidemia). (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Association with other disorders'.)
Management of patients with NAFLD and diabetes includes optimization of blood glucose control. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and 'Patients with NASH and diabetes' below.)
Most patients with NAFLD who have hyperlipidemia 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 NAFLD. We recommend weight loss for all patients with NAFLD who are overweight (body mass index [BMI] >25 kg/m2 ) or obese (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 NAFLD [7-10]. 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.
Initial lifestyle interventions — We advise patients who are overweight or obese 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 NASH, 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 'Nonalcoholic fatty 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 women and <30 for men) after achieving the weight loss goal, we advise patients to lose additional weight. (See 'Laboratory monitoring' below.)
For patients with nonalcoholic steatohepatitis (NASH) 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 NALFD activity score (NAS), which is used to grade disease activity [11]. The NAS is discussed separately. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'NAFLD activity score'.)
In another trial including 31 overweight and obese patients (BMI 25 to 40 kg/m2) with biopsy-proven NASH, 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) [8]. 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 NAFLD [12,13]. In a longitudinal study of the National Health and Nutrition Examination Survey including 2793 individuals with NAFLD, 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) [13]. 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 NASH 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 obese patients with NAFLD, and histologic improvement has been observed postoperatively [14-24]. 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'.)
In a systematic review that included 21 observational studies of bariatric surgery in patients with NASH, an improvement in steatosis was reported in 18 studies, decreased inflammation was reported in 11 studies, and improvement in fibrosis score was reported in six studies [25]. However, in four studies there was some worsening of fibrosis.
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. Selecting patients for therapy and choosing a drug for weight loss are discussed separately. (See "Obesity in adults: Drug therapy".)
Potential pharmacologic therapies — Options for pharmacologic, liver-targeted therapy for NAFLD are limited (eg, vitamin E, some insulin sensitizers), and we do not use them in all patients. We reserve pharmacologic therapy for patients who do not achieve their weight loss goals and who have biopsy-proven NASH 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 NASH. 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 levels or histologic findings, often with conflicting results [26].
Patients with NASH but without diabetes — For patients with biopsy-proven NASH 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) [27].
We do not use pioglitazone for patients with NASH but without diabetes mellitus because of its potential adverse effects as discussed below, although society guidelines state that pioglitazone may be used for these patients [27]. (See 'Patients with NASH and diabetes' below.)
Some, but not all, randomized trials support the use of vitamin E for NASH, but the conflicting findings may be related to differences in trial design [28-35]. 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 [26].
However, the largest randomized trial included in the meta-analysis (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH) did suggest a benefit with vitamin E. The trial included 247 adults with NASH without diabetes who were randomly assigned to pioglitazone (30 mg daily), vitamin E (800 international units daily), or placebo for 96 weeks [30]. 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) [36]. This is consistent with observational studies that suggested improvement in aminotransferase levels in patients with NASH who received vitamin E [37]. 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 NASH 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 NASH and diabetes — For patients with diabetes mellitus, the presence of NASH 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 [27,38,39], 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 NASH who cannot take metformin or need additional glucose-lowering therapy. In this setting, pioglitazone and glucagon-like peptide-1 (GLP-1) receptor agonists (eg, liraglutide) are reasonable options.
In patients with diabetes mellitus and biopsy-proven NASH, pioglitazone improves fibrosis as well as inflammation and steatosis. GLP-1 receptor agonists also appear to provide some benefits for patients with NASH. 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 NASH:
●Pioglitazone – Thiazolidinediones, and specifically pioglitazone, improve liver biochemical and histologic parameters in patients with NASH [28,30,40-46]. The effect of thiazolidinediones on histologic parameters in NASH was examined in a meta-analysis of four trials that compared thiazolidinediones with placebo in 334 patients with NASH [47]. 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 [40].
●GLP-1 receptor agonists [48-50]:
•Liraglutide – In a trial including 52 patients with NASH 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 [48]. NASH 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 NASH and liver fibrosis of stage F1, F2 or F3, semaglutide (0.4 mg once daily) resulted in higher rates of histologic resolution of NASH compared with placebo after 72 weeks (59 versus 17 percent; OR 6.87, 95% CI 2.60-17.63) [50]. 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 NASH 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 NAFLD is likely related to the role insulin resistance plays in the development of NAFLD. (See "Pathogenesis of 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 [30,36]. This is consistent with recommendations from the AASLD [27].
Therapies with uncertain benefit — Other medical therapies have been examined for the treatment of NAFLD, but none has been studied sufficiently to recommend its use as treatment for fatty liver or NASH:
●Atorvastatin – Pilot studies found a benefit from atorvastatin on aminotransferase levels in patients with NAFLD [51,52]. 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 [53]. 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 NAFLD based upon imaging criteria. After a mean of 3.6 years of follow-up, fewer patients in the treatment arm still had NAFLD 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 NAFLD 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 NAFLD [54,55]. 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 [55]. 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 [55-58].
●Aspirin – Limited data suggest that daily aspirin use is beneficial for patients with NAFLD [59-61]. In the enrollment phase of a prospective cohort study including 361 patients with biopsy-proven NAFLD, daily aspirin users were less likely to have NASH (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 [59]. 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 biochemical and function tests".)
Monitoring for fibrosis — Our approach to monitoring patients for advanced fibrosis depends on whether they have biopsy-proven NASH and if they achieved weight loss goals and normalization of serum aminotransferases:
●Patients with biopsy-proven NASH – For patients with biopsy-proven NASH, 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 NASH and no fibrosis or minimal fibrosis have an excellent prognosis and thus, close follow-up is not needed [62].
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 NASH – We do not routinely obtain a noninvasive assessment for fibrosis in patients with nonalcoholic fatty liver but without biopsy-proven NASH. 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 (vibration-controlled transient elastography, ultrasound shear wave or 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 [63]. In a prospective study of 120 patients with biopsy-proven NAFLD, 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. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Vibration controlled transient elastography'.)
SPECIAL POPULATIONS
Patients with cirrhosis — The management of cirrhosis due to NAFLD 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 NAFLD are at risk for advanced fibrosis, defined histologically as stage F2 or higher (table 1). 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 NAFLD [62,64,65]. (See 'Monitoring for fibrosis' above.)
While the risk of disease progression among patients with NAFLD has been evaluated in multiple studies, the results have been variable, and the risk of developing advanced fibrosis among patients with NAFLD is unclear [1-4,66-74]. A meta-analysis that included 11 studies looked at progression to fibrosis in 366 patients with NAFLD [75]. 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 nonalcoholic steatohepatitis are at higher risk [76]. In addition, some patients with fibrosis show regression of their disease [66-68].
In a cohort study of 129 patients with NAFLD 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 [3]. 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 'Nonalcoholic fatty liver disease'.)
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 [77,78].
•Diabetes mellitus [64,79].
•Older age (eg, ≥50 years) [68,80].
●Disease-related risk factors
•Histologic evidence of inflammation on liver biopsy (see 'Hepatic inflammation' below).
•Ballooning degeneration plus Mallory hyaline or fibrosis on biopsy [64].
•Elevated serum aminotransferases (eg, ≥2 times the upper limit of normal) [77,79-81].
Coffee consumption has been associated with a lower risk of progressing to fibrosis [82].
Several statistical models have been described to predict fibrosis, but none have been extensively validated [77,81,83-85].
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 men and >7 drinks per week or >3 drinks on a given day for women) [5]. (See 'General measures for all patients' above and "Risky drinking and alcohol use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis", section on 'Terminology'.)
Heavy alcohol use among patients with NAFLD is associated with hepatic steatosis, hepatic injury, and fibrosis progression [6]. In a study of 71 patients with NAFLD followed for a mean of 14 years, 17 patients (24 percent) had fibrosis progression [6]. Heavy episodic drinking (defined in this study as more than 60 grams of alcohol on one occasion for men or 48 grams for women) was more common in those with fibrosis progression than in those without progression (47 versus 11 percent).
We also suggest that patients with NAFLD 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 lacking. 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 who are obese) is associated in hepatic injury [86,87]. In a cohort study of 285 patients with NAFLD, 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 NASH resolution. In addition, moderate alcohol consumption does not appear to lower the risk of cardiovascular disease for patients with NAFLD, in contrast to the general population [88]. (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 [89,90]. This was seen in a cross-sectional study that compared 251 lifetime nondrinkers with NAFLD with 331 modest drinkers with NAFLD [89]. 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 [68]. 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 NASH-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 NAFLD are at higher risk for HCC compared with patients without cirrhosis [91,92]. In a systematic review of 61 studies and case series of patients with NAFL or NASH, the risk of HCC among those with cirrhosis ranged from 2.4 percent over seven years to 12.8 percent over three years [91]. 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 NASH-related cirrhosis have lower rates of HCC surveillance compared with patients with cirrhosis from other etiologies such as hepatitis C virus infection [93-95].
Mortality — Whether patients with NAFLD have increased overall mortality rates compared with the general population is not clear. While small population-based studies have suggested a mortality risk [65,96,97], 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 NAFLD and advanced fibrosis, as determined by the NAFLD activity score, were 30 and 10.3 percent, respectively [98]. Compared with individuals without NAFLD, overall mortality was lower in NAFLD participants without fibrosis (HR 0.41, 95% CI 0.22-0.76), while mortality was higher in NAFLD 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 NAFLD 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) [99]. 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 NAFLD. A previous study (NHANES III), which showed similar trends in mortality, found that the increase in mortality in NAFLD patients with fibrosis (as measured by the NAFLD fibrosis score) was due almost exclusively to cardiovascular causes (HR 3.46, 95% CI 1.91-6.25) [100]. Risk factors for cardiovascular disease (eg, diabetes, hyperlipidemia) can be identified and managed in patients with NAFLD. (See 'General measures for all patients' above.)
Patients with NASH are at increased risk for liver-related death compared with patients with fatty liver but without NASH [65,96,101,102].
Liver decompensation — Fibrosis stage has been associated with risk of liver decompensation. In a study including 1773 adults with NAFLD 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) [99].
WHEN TO REFER — Referral to a hepatologist is indicated for patients with NAFLD 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: 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: Nonalcoholic fatty liver disease (The Basics)").
●Beyond the Basics topics (see "Patient education: Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH) (Beyond the Basics)").
SUMMARY AND RECOMMENDATIONS
●General measures – The following general measures apply to patients with nonalcoholic fatty liver disease (NAFLD) (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 NAFLD. 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 NAFLD, 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 NAFLD, 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 NAFLD. (See 'General measures for all patients' above and 'Alcohol use' above and "Risky drinking and alcohol use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis".)
●Medical therapy
•Patients with NASH but without diabetes mellitus – For patients with biopsy-proven nonalcoholic steatohepatitis (NASH) 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 NASH but without diabetes' above.)
•Patients with NASH and diabetes mellitus – For patients with NASH and diabetes mellitus, the presence of NASH 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 NASH 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 NASH 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 NAFLD 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 biochemical and function tests".)
●Monitoring for fibrosis – For patients with biopsy-proven NASH, 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.
