Definition & Etiology

Definition & Etiology

William D. Carey, MD


Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of conditions associated with lipid deposition in hepatocytes. It ranges from simple steatosis (fatty liver), to nonalcoholic steatohepatitis (NASH), fatty changes with inflammation and hepatocellular injury or fibrosis, to advanced fibrosis and cirrhosis at its most severe. Although steatosis is a benign condition, NASH can progress to fibrosis and lead to end-stage liver disease. NAFLD is strongly associated with obesity and insulin resistance and is currently considered by many to be the hepatic component of metabolic syndrome. NASH cirrhosis is now the second-most-common indication for liver transplantation in the United States after alcoholic cirrhosis, representing 21% of transplants. Because NAFLD resembles alcoholic liver disease histologically but occurs in people who drink little or no alcohol, excessive daily alcohol consumption must be ruled out before making the diagnosis. Other conditions (Table 1) leading to fat deposition in the liver must be excluded by history, physical examination, and appropriate testing.

Table 1: Conditions associated with macrovesicular steatosis

Nonalcoholic fatty liver disease

Alcoholic liver disease

Medications

  • Amiodarone
  • Calcium channel blockers
  • Corticosteroids
  • Coumadin
  • Estrogens
  • Isoniazid
  • l-asparaginase
  • Methotrexate
  • Perhexiline
  • Tamoxifen
  • Troglitazone
  • Vitamin A

Hepatitis C

Wilson disease

Nutritional factors (malnutrition/malabsorption)

  • Rapid weight loss
  • Total parenteral nutrition
  • Starvation
  • Protein-calorie malnutrition
  • Inflammatory bowel disease

Inherited metabolic disorders

  • Abetalipoproteinemia
  • Cystic fibrosis

Inherited syndromes associated with obesity and insulin resistance

  • Prader-Willi syndrome
  • Lipodystrophies
  • Hypopituitarism

Small intestinal bacterial overgrowth (SIBO)

Toxic mushroom ingestion

Epidemiology

Epidemiology

NAFLD is one of the most common liver diseases and NASH is now the leading cause of cirrhosis. The prevalence of NAFLD is affected by many factors, including genetics and environment. The risk of liver disease increases with body mass index (BMI). NAFLD is associated not only with obesity but also being overweight. The prevalence of overweight persons (BMI ≥25 kg/m) in the US has risen to more than 65%, and obesity (BMI ≥30 kg/m) is now present in more than 30% of the adult US population according to the Centers for Disease Control (CDC). NAFLD is estimated to occur in as much as 30-40% of the general population in the US. NASH is thought to occur in approximately 5% of the US population but may be found in more than 25% of obese persons. The prevalence of NAFLD is increased in men, individuals >40 years, and those with components of the metabolic syndrome, in particular type 2 diabetes mellitus. According to the CDC, nearly 26 million Americans have diabetes and an estimated 79 million adults have pre-diabetes. Hepatic steatosis is seen in up 80% of those with type 2 diabetes. NAFLD has been observed in all ethnic groups with the highest prevalence seen in Hispanics followed by Non-Hispanic whites.

Pathophysiology & Natural History

Pathophysiology & Natural History

Development of NASH appears to require at least 2 liver insults. With the initial insult, macrovesicular steatosis occurs secondary to excessive triglyceride accumulation in the liver. Insulin resistance and subsequent hyperinsulinemia appear to lead to alterations in the hepatic pathways of uptake, synthesis, degradation, and secretion of free fatty acids and ultimately to accumulation of lipids in the hepatocytes. These changes make the liver susceptible to a second insult, resulting in an inflammatory response and progression of liver damage. Oxidative stress, mainly caused by mitochondrial dysfunction, and proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, are believed to play an important role in the progression of liver damage in NAFLD. Potential oxidative stressors include hepatic iron, leptin, antioxidant deficiencies, and intestinal bacteria. Hepatocyte apoptosis, an organized form of cell death, has been identified as a potential key component of the second insult involved in NAFLD progression.

Overall, morbidity and mortality have been shown to be significantly higher in those with NASH compared with the general population. Coronary artery disease and malignancy followed by liver-related mortality are the most common causes of death in people with NASH. Data suggest that the natural history of NAFLD is determined by the severity of the histologic damage. Most with NAFLD have simple steatosis without inflammation and generally have a benign clinical course. Of those with NASH, 15% to 25% progress to cirrhosis, generally over a 10-to-20-year period. At the time of initial biopsy, as many as one-third of those with NASH have advanced hepatic fibrosis, whereas 10% to 15% have well-established cirrhosis. It is now recognized that a large portion of those with cryptogenic cirrhosis have “burned-out” NASH, in which the histologic feature of steatosis or steatohepatitis is replaced by a bland cirrhosis. NASH cirrhosis is a risk factor for development of hepatocellular carcinoma (HCC). Studies report an incidence of HCC up to 0.5% in those with NAFLD and up to 2.8% in those with NASH over a 20-year period. Data from Japan suggest that the cumulative incidence of HCC at 5 years may be as high as 15%.

Diagnosis

Diagnosis

Signs and Symptoms

Most with NAFLD are asymptomatic, and liver disease is often discovered when laboratory examination incidentally reveals elevated aminotransferase levels. It is the most common cause of unexplained persistent elevation of liver enzyme levels after hepatitis and other chronic liver diseases have been excluded. When symptomatic, the most common symptoms that bring NAFLD to medical attention are vague, such as malaise, fatigue, or pruritis. Hepatomegaly may be found on clinical examination. When cirrhosis appears, stigmata of chronic liver disease, such as spider angiomas, ascites, splenomegaly, palmar erythema, and asterixis, can be present. Individuals may present with complications of decompensated cirrhosis (e.g., jaundice, variceal bleeding or hepatic encephalopathy). Most have associated features of metabolic syndrome (Table 2): obesity (47% - 90%), diabetes mellitus (28% - 55%), and variable incidences of hyperlipidemia and hypertension. There is emerging evidence that obstructive sleep apnea, polycystic ovarian syndrome, colorectal cancer, and osteoporosis are linked to NAFLD as well.

Table 2: Components of metabolic syndrome. Metabolic syndrome is diagnosed by the presence of 2 or more of these parameters.

Impaired glucose tolerance Fasting blood glucose level ≥110 mg/dL or taking glucose-lowering medication
Hypertension ≥130/80 mm Hg
Hypertriglyceridemia >150 mg/dL
Low high-density lipoprotein level <40 mg/dL for men
<50 mg/dL for women
Abdominal (central) obesity Waist circumference >102 cm (40”) for men
Waist circumference >88 cm (35”) for women

© 2015 The Cleveland Clinic Foundation.

It is particularly relevant to inquire about excess alcohol consumption, defined as >30 g/day for men and >20 g/day for women within the past 5 years; 350 mL (12 oz) of beer, 120 mL (4 oz) of wine, and 45 mL (1.5 oz) of hard liquor each contain 10 g of alcohol, to define the nonalcoholic nature of the condition.

Laboratory Studies

In someone with suspected NAFLD, testing should include levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Mild to moderate elevation of serum aminotransferase levels is a common finding (mean range 100-200 IU/L). Generally, the ratio of AST to ALT is <1, but this ratio increases as fibrosis advances. Liver enzyme levels are normal in a large percentage of those with NAFLD, and, as such, do not exclude the presence of disease. Serum alkaline phosphatase and g-glutamyl transpeptidase (GGT) levels may also be mildly elevated, but generally not more than 2-3 times the upper limit of normal. Given that more than 80% of those with NAFLD have components of metabolic syndrome, serum levels of triglycerides as well as fasting glucose or hemoglobin A1c should be checked. Albumin, bilirubin, and platelet levels are usually normal unless the disease has progressed to cirrhosis. Other infectious and inherited causes of liver disease should be excluded in those being evaluated. Some with NAFLD have low titers of autoimmune antibodies (anti-nuclear and anti–smooth muscle antibody) but the significance of these markers is still unclear. Elevated ferritin levels may be present and evaluation of such is described in the chapter on Hematochromatosis.

Imaging

Liver ultrasound is useful for assessing steatosis. Fatty infiltration of the liver produces a diffuse increase in echogenicity (a bright liver) and vascular blurring (Figure 1). Unfortunately, ultrasound cannot rule out inflammation or fibrosis and its sensitivity drops sharply when fewer than one-third of hepatocytes contain fat droplets. Both computed tomography (CT) and magnetic resonance imaging (MRI), in particular magnetic resonance spectroscopy, are more sensitive modalities for quantifying steatosis, however, none of these imaging techniques has sufficient sensitivity and specificity for staging the disease and cannot distinguish between simple bland steatosis and NASH with or without fibrosis. Neither of these modalities are commonly used in clinical practice. Elastography has emerged as a non-invasive means of assessing fibrosis by measuring liver stiffness, which increases with increased fibrosis. Developed initially to diagnose significant fibrosis in chronic Hepatitis C, these modalities have been refined to be used in the diagnosis of NAFLD. Vibration-controlled transient elastography (VCTE, FibroScan®) is the most commonly used modality followed by the much less utilized acoustic radiation force impulse (ARFI). VCTE provides a controlled attenuation parameter (CAP) score, a measure of the degree of steatosis (Table 3) measured in decibels per meter (dB/m) as well as a fibrosis score (Table 4) measured in kilopascals (kPa), a measure of the degree of liver stiffness. A 2019 prospective analysis of those with NAFLD found AUROC values ranging from 0.70 to 0.87 for CAP score and 0.77 to 0.89 for liver stiffness by FibroScan compared to liver biopsy. These modalities are unable to delineate steatosis from steatohepatitis or follow longitudinal changes in fibrosis.

Figure 1: Sonographic features of NAFLD. A) Normal liver. B) Hepatic steatosis

Figure 1: Sonographic features of NAFLD. A) Normal liver. B) Hepatic steatosis


Table 3: Fibrosis score in VCTE for NAFLD

Fibrosis Score Liver Stiffness Degree of Scarring  
F0 – F1 2 – 7 kPa No or mild liver scarring Early
F2 7.5 – 10 kPa Moderate liver scarring Clinically significant
F3 10 – 14 kPa Severe liver scarring Advanced
F4 >14 kPa Advanced liver scarring (cirrhosis) Advanced

 

Table 4: Steatosis grade in VCTE for NAFLD

Steatosis Grade CAP score (dB/m) Percent of Liver with Fatty Change
S1 238 – 260 11 – 33%
S2 261 – 290 34 – 66%
S3 >290 >66%

 

Liver Biopsy

Biopsy remains the most accurate means to grade the severity of the disease and thus estimate prognosis. Biopsy is helpful in distinguishing steatosis from steatohepatitis, assessing the degree of fibrosis, and may be helpful in ruling in or out alternative causes of liver disease. In addition, histology permits the monitoring of disease progression and the response to therapy, although this is rarely used in clinical practice. The spectrum of abnormalities varies from simple bland steatosis to NASH, in which steatosis is associated with mixed inflammatory cell infiltration and liver injury (Figure 2). Cell injury is manifested by hepatocyte ballooning. Liver biopsies are evaluated for the percentage of surface area involved with steatosis, lobular inflammation, and hepatocellular ballooning. These unweighted components are evaluated as part of the NAFLD Activity Score (Table 5). An NAS <3 corresponds to simple steatosis. A score of 3 - 4 is indeterminate. A score of ≥5 represents NASH. Biopsies are also evaluated for the degree and extent of fibrosis (Table 6). Stage 1 represents portal/perisinusoidal fibrosis, stage 2 represents both portal/periportal and perisinusoidal fibrosis, stage 3 represents bridging fibrosis, and stage 4 represents cirrhosis.

 

Figure 2: Spectrum of disease in NAFLD. A: Simple steatosis. B: Nonalcoholic steatohepatitis (NASH). C: Cirrhosis. (Image courtesy of Lisa M. Yerian, MD)

Figure 2: Spectrum of disease in NAFLD. A: Simple steatosis. B: Nonalcoholic steatohepatitis (NASH). C: Cirrhosis. (Image courtesy of Lisa M. Yerian, MD)


Table 5: Biopsy NAFLD Activity Score (NAS)

Score Steatosis Lobular Inflammation Ballooning Degeneration
0 <5% None None
1 5 – 33% <2 foci/200x field Few
2 34 – 66% 2-4 foci/200x field Many
3 >66% >4 foci/200x field  

 

Table 6: Biopsy Fibrosis Score

Stage Histologic Findings
1a Mild pericellular fibrosis
1b Moderate pericellular fibrosis
1c Portal/periportal fibrosis
2 Pericellular and portal/periportal fibrosis
3 Septal/bridging fibrosis
4 Cirrhosis

NAFLD is histologically indistinguishable from liver damage resulting from excessive alcohol consumption; both produce macrovesicular steatosis. In fact, a wide range of conditions can produce similar histologic findings (Table 1).

Despite the advantages of liver biopsy, its overall role in the evaluation of those with NAFLD is unsettled, in large measure because of its risks and poor patient acceptance. In those with risk factors for NAFLD (i.e., metabolic syndrome), 3 to 6 months are often allowed for a trial of weight loss and for possible improvements in imaging studies and biochemical markers of liver disease. In the subset of individuals most likely to have NASH or advanced disease (e.g., ≥45 years, morbidly obesity, type 2 diabetic, thrombocytopenic, low albumin, AST/ALT ratio ≥1, evidence of portal hypertension) and in those with an unclear diagnosis, a liver biopsy should be considered earlier. A repeat liver biopsy in those with NASH in 3 - 5 years should be considered to monitor disease progression.

Management

Management

The goal of treatment is to improve steatosis and prevent the development of fibrosis, which can lead to cirrhosis and its complications. Since the prognosis of NASH depends on risk factors (e.g., obesity, insulin resistance, type 2 diabetes), addressing these conditions has been the focus of treatment. Broadly, medications aimed at improving liver disease should be limited to those with biopsy-proven NASH and fibrosis. Current treatment guidance stems from the American Association for the Study of Liver Diseases (AASLD) in conjunction with the American College of Gastroenterology (ACG) and the American Gastroenterological Association (AGA), published 2012 and most recently updated January 2018 as well as the European Association for the Study of Liver diseases (EASL) guidelines published 2016. Management strategies are summarized in Table 7 at the end of this chapter.

Weight Loss

Weight reduction has been widely studied in adults with NASH and has been shown to improve not only serum aminotransferases but also liver histology. A 2012 meta-analysis of 8 randomized controlled trials (RCTs) demonstrated that individuals with ≥5% weight loss had reduction in steatosis. This was supported by a 2015 prospective study with paired liver biopsies. Greater weight loss (>10% body weight) has been shown to improve fibrosis and portal inflammation. Adherence to the Mediterranean diet, a diet high in monounsaturated fatty acids, was shown to reduce hepatic steatosis on imaging when compared with a low fat, high carbohydrate diet in a 2013 6-week cross-over comparison. Slow, consistent weight loss (to a target of 7-10%) through a diet designed to produce a caloric deficit of 750-1000 kcal/day is advised. Reduction of dietary carbohydrates, in particular dietary fructose, is the most beneficial and has been found to improve the lipid profile in those who are overweight. High- to moderate-intensity exercise (30 minutes per day, 3 - 5 times per week) has also been advocated to reduce the risk of comorbidities associated with obesity. A 2011 study showed a reduction in hepatic steatosis with exercise but no improvement in fibrosis or NAFLD activity scores. Exercise has also been shown to decrease serum aminotransferases. Realistically, individuals should be encouraged to incorporate moderate activity into everyday life (e.g., climbing stairs instead of taking an elevator, walking instead of driving).

Pharmacologic treatment of obesity in NASH is not recommended in current guidelines. Several drugs have been studied, including sibutramine, a serotonin reuptake inhibitor, and orlistat, which reduces fat absorption. Both of these have been shown to improve liver enzyme levels and steatosis. A meta-analysis of rimonabant, a cannabinoid-1-antagonist, showed increased adverse events and has not been recommended.

Weight loss is difficult to achieve through diet and exercise and even harder to sustain. Consideration for bariatric surgery is recommended for those with a BMI >40 kg/m2 or for those with a BMI of >35 kg/m2 and obesity-related comorbidities, but is not yet an established option for the treatment of NASH itself. Improvement in steatosis and histopathologic features such as portal inflammation and balloon degeneration has been demonstrated in prospective studies but it was thought until recently that fibrosis would not improve. In a large meta-analysis published in 2008, authors in Texas compiled 15 studies evaluating the role of bariatric surgery in NAFLD for a total of 766 paired liver biopsies. Nearly 92% of pooled subjects had improvement or resolution in steatosis, 81% steatohepatitis, and 65% fibrosis. Nearly 70% had complete resolution of NASH. In a 2009 prospective study in France, 381 morbidly obese subjects underwent bariatric surgery and had repeat liver biopsies performed at 1 and 5 years post-operatively. The percentage of those with steatosis improved (from 37% to 16%) but levels of fibrosis increased (27% to 36%) and inflammation remained unchanged at 5 years. The percentage of those with probable or definite NASH did decrease from 27% to 14% over the study period. The authors found that many of these changes were seen by the first year post-operatively and were maintained for the entire 5-year period. In a 2019 study, 65 subjects who had undergone bariatric surgery (53 gastric bypass, 12 sleeve gastrectomy) and underwent repeat liver biopsy an average of 6 years post-operatively showed that more than half with severe fibrosis had improvement in liver histology. Further prospective, RCTs are needed to make definitive recommendations regarding bariatric surgery. Additionally, the safety of bariatric surgery in those with cirrhosis is still under investigation. A review of mortality data from the Nationwide Inpatient Sample showed higher mortality (double) in those with compensated cirrhosis and significantly higher mortality in those with decompensated cirrhosis (some 21 times) compared to those without chronic liver disease.

Statins

Those with NAFLD often have high triglyceride levels, decreased low density lipoprotein (LDL), and a high apolipoprotein B to apolipoprotein A1 ratio. Studies have looked at the effect of statins on improvement in lipid profile in those with NAFLD and effect on aminotransferase levels. Although one of the most common side effects of statins is aminotransferase elevation, evidence suggests that those with elevated baseline transaminase levels in the setting of NAFLD who receive statin treatment do not have a higher incidence of liver enzyme level elevation or hepatotoxicity than control subjects who do not receive statins. This has been shown in two post-hoc analyses, one of the cardiovascular outcomes study The Greek Atorvastatin and Coronary Heart Disease Evaluation (GReACE) in 2010, and of the Initiating Dialysis Early and Late (IDEAL) trial. Both showed that those with NAFLD had improvement in their serum aminotransferases on moderate-intensity dose atorvastatin, and showed a greater reduction with a high-dose statin v moderate-intensity dosing. Fewer than 1% of subjects in the GReACE study needed to discontinue statin use due to aminotransferase elevation greater than three times the upper limit of normal. Additionally, statins in those with NAFLD were found to reduce cardiovascular events twice as much as in those with normal liver function. A 2011 trial of 43 subjects noted improvements in complete lipid profile (LDL, total cholesterol, and triglycerides) for those with NAFLD on statins without an impact (either positively or negatively) on aminotransferases. A small 2012 trial of biopsy-proven NASH subjects (without a comparator group) in Japan noted improvements in aminotransferases, GGT, and lipid profile for those on atorvastatin for one year, as well as NAFLD Activity Scores (incorporating hepatocyte ballooning and inflammation). The 2012 PITCH trial in Korea randomized 189 subjects with NAFLD to 12 weeks of pitavastatin or atorvastatin, showing improvement in lipid profile and no difference between the two statins. The pravastatin group was also observed to have reduced steatosis on serial CT imaging of the liver and reduction in ALT, but not AST or GGT. The efficacy of statins in NAFLD were compared to insulin sensitizers metformin and pioglitazone in a 2016 trial. The authors found that ALT was reduced in the metformin and pioglitazone groups and increased in the statin group, but never more than three times the upper limit of normal. Both rosuvastatin and pioglitazine groups had reduction in steatosis on serial abdominal ultrasound imaging and the lipid profiles were improved in all three groups, but most noticeably in the statin group.

A few studies have evaluated changes in histology in those with NASH on statins. Two studies from Japan, first in 2011, evaluated pitavastatin and found no change in steatosis, fibrosis, or inflammation in the 13 who underwent repeat liver biopsy. Just over half of subjects did show improvement in NAFLD Activity Score though. The second trial in 2012 looked at rosuvastatin and found no difference in NAFLD Activity Score or fibrosis stage of the 9 who had repeat liver biopsies. A 2015 study in Greece showed resolution of NASH in 19 of the 20 undergoing repeat biopsy after treatment with rosuvastatin. These studies are promising but further, larger, prospective, randomized trials are needed to evaluate the appropriate statin choice and dose for those with NAFLD.

A recent study in Taiwan evaluated 18,000 non-cirrhotics with NAFLD in a national database for characteristics associated with HCC and found decreased incidence of HCC for the one-third of subjects on statins, positing that there may be an HCC-protective effect from statin use in this group, but further studies are needed.

Other Lipid-Lowering Agents

A trial of 186 patients in 2006 compared those taking atorvastatin, fenofibrate, or both in combination looked at lab parameters and ultrasound findings only (not histology) and saw no significant difference between trial groups after 54 weeks of treatment. Those in the fibrate group were noted to have higher triglyceride levels at the end of the trial. Given the small sample sizes both studies were felt to be at high risk of bias. Fibrates, in another randomized controlled trial, did not show any histologic benefit. Probucol, a lipid-lowering drug, has shown improvement in aminotransferases but also reduction in HDL levels. Neither are currently recommended in US or European treatment guidelines. Monounsaturated fatty acid intake improves cardiovascular risk and lipid profiles, thus has been hypothesized to be of benefit in NAFLD. Polyunsaturated fatty acids, studied in 3 randomized controlled trials, have been shown to improve aminotransferases and hepatic steatosis, however omega-3 fatty acids are not recommended for the treatment of NAFLD in current guidelines. Omega-3 fatty acids may be of benefit in treating hypertriglyceridemia in this group though.

Vitamin E

Several trials of tocopherol (vitamin E) for patients with NAFLD have shown clinical benefit. The PIVENS (Pioglitazine, Vitamin E, or Placebo for NASH) trial showed that vitamin E (800 IU/d) led to an improvement in NASH compared with placebo as well as a reduction in aminotransferases. However, a controversial report has shown a mild increase in all-cause mortality in people taking high-dose vitamin E (≥800 IU/d) as a health supplement, although some have criticized this study for failing to consider confounders such as concomitant vitamin use (e.g., vitamin A) as well as smoking. An increased risk of prostate cancer in men was also demonstrated. One study found that a daily dose of the natural form of vitamin E, the type that comes from food sources, improved NASH in study participants overall. Vitamin E is considered a first-line therapy in non-diabetics with biopsy-proven NASH in current guidelines although it is not advised in those with diabetes, cirrhosis, or NAFLD without a liver biopsy.

Antioxidants

Oxidative stress has been hypothesized to contribute to the progression of NAFLD to NASH and to worsen insulin resistance. For this reason, antioxidant treatment to reduce this stress and slow the progression of the disease has been studied, such as pentoxifylline. This medication inhibits a number of proinflammatory cytokines and is thought to have hepatoprotective effects. One small randomized study showed improvement in histologic features of NASH when compared with placebo but it is not currently guideline-recommended treatment. Betaine and N-acetylcysteine have shown promising effects, but larger trials are needed.

Ursodeoxycholic Acid

Several small, proof-of-concept studies suggest a role of ursodeoxycholic acid in the improvement of aminotransferases and hepatic steatosis in NASH, but the only large RCT has not shown histologic benefit. Guidelines do not currently recommended ursodeoxycholic acid in the treatment of NAFLD.

Obeticholic Acid

Obeticholic acid, a semi-synthetic bile acid analog that functions as a farnesoid X receptor agonist is currently FDA approved for the treatment of primary biliary cholangitis. The FLINT (Farnesoid X Ligant Receptor Obeticholic Acid in NASH Treatment) trial found that obeticholic acid was associated with improved liver function in people with NASH but was also associated with worsening pruritis and elevated total cholesterol levels. An interim analysis published in late 2019 from a large, industry-funded, Phase III, multi-center trial has shown similar NASH resolution rates between placebo and obeticholic acid groups but improvement in fibrosis for more subjects (18% at 10mg per day dosing, 23% at 25mg per day dosing v 12% in placebo) using obeticholic acid at 18 months (of a planned 4-year trial). Treatment groups have had higher rates of pruritis with a dose-response effect. More research is needed to determine whether OCA is a safe and effective treatment for NASH and to fully understand how OCA affects cholesterol. It is still unclear which patients are most likely to benefit from the use of OCA. Of note, the FDA advisory panel recommended FDA approval for the usa of OCA for the treatment of NASH, and will likely receive approval in 2020. The cost of the medication may limit its use if approved.

Alcohol Consumption

“Heavy” drinking has been defined as >4 standard drinks per day (30g) or >14 standard drinks per week in men and >3 standard drinks (20g) per day or >7 standard drinks per week in women. In order to establish a diagnosis of NAFLD a history of heavy drinking must be excluded. It is unclear whether moderate alcohol consumption may be beneficial in NAFLD as it is in cardiovascular health or if those with metabolic risk factors may be particularly sensitive to alcohol-induced liver injury. A number of recent studies have aimed to evaluate this.

One 2018 study from Australia noted that modest alcohol consumption (defined as <70g weekly and the absence of binge drinking) was associated with lower mean fibrosis stage on liver biopsy and a decreased risk of advanced fibrosis compared to lifelong abstinence from alcohol consumption. Exclusive wine drinkers had lower mean fibrosis stage and lower odds of advanced fibrosis compared to lifetime abstinent subjects. In a recent 2019 study, the authors identified patients with NAFLD using the Hepatic Steatosis Index biochemical model in the NHANES national prospective cohort and merged this with mortality data from the National Death Index to evaluate the effect of alcohol consumption on survival. In a model adjusted for age, sex, and smoking history, drinking 0.5 - 1.5 drinks per day decreased the risk of overall mortality by 41% compared with not drinking. Drinking ≥1.5 drinks per day though showed a trend toward harm. After adjustment for race, physical activity, educational attainment, diabetes, fiber, and polyunsaturated fatty acid intake, drinking 0.5 - 1.5 drinks per day continued to show a significant protective effect and drinking ≥1.5 drinks per day continued to show a significant harmful effect on mortality. Some have questioned whether this mortality benefit can be entirely attributed to improvement in cardiovascular outcomes as opposed to NAFLD itself. Conversely, a 2018 Finnish population-based study that calculated “average” alcohol use by extrapolating use in the prior one year noted that even moderate alcohol use was still a significant risk factor for incident liver disease (defined as first hospitalization for liver disease, liver-related death, or diagnosis with liver cancer).

Further studies are needed to demonstrate that “moderate” drinking is beneficial for those with NAFLD and these data should be weighed against the risk of chronic liver disease with excess drinking. Current guidelines recommend alcohol intake be kept <30g per day in men and <20g per day in women, but do not encourage moderate alcohol consumption.

Coffee

An inverse association between coffee consumption and severity of fibrosis has been seen in studies of chronic liver disease. A 2017 meta-analysis of available data, looking at 5 studies, revealed a decreased risk of NAFLD among coffee drinkers and a slower rate of progression of fibrosis among those with NAFLD, but identified a number of potential confounders, (e.g., lower BMI in coffee drinkers), and notes that the amount of coffee consumed varied widely between studies. Moderate coffee consumption may be reasonable to recommend to those with NAFLD but further randomized studies are needed to demonstrate benefit.

Insulin-Sensitizing Agents

Those with comorbid NASH and diabetes mellitus are at higher risk of developing more-aggressive disease. Insulin-sensitizing agents have been tested in adults. Metformin, a biguanide oral anti-diabetic agent, lowers hepatic glucose production and promotes glucose uptake in the muscles. Randomized controlled trials have shown improved serum aminotransferases and insulin resistance but inconsistent effects on liver histology. Metformin is not currently recommended for treating NASH.

Peroxisome proliferator-activated receptor (PPAR) gamma agonists have been shown to improve insulin resistance and liver histology by promoting redistribution of triglycerides from the liver and muscle into proliferating adipocytes. One randomized controlled, double-blind clinical trial in 2010 on the use of pioglitazone, vitamin E, or placebo for the treatment of non-diabetics with NASH (PIVENS) showed no difference in the rate of improvement in NASH compared with placebo but it did show a reduction in aminotransferases and hepatic steatosis. Pioglitazone was found to improve liver histology in those with and without type 2 diabetes mellitus with NASH. Longer-term trials suggest that prolonged therapy with thiazolidinediones are needed to maintain this histologic improvement. Rosiglitazone was found to improve hepatic steatosis but did not affect inflammation or fibrosis. Hepatotoxicity has been described with thioglitazones, and a more common side effect is paradoxical weight gain and fat redistribution. Although controversial, increased risk of cardiovascular events and bone loss with the use of rosiglitazone as well as of increased risk of heart failure with pioglitazone have been described. Pioglitazone can be used for treatment of biopsy-proven NASH in those with and without diabetes mellitus, but the potential risks need to be discussed with each patient.

One 2016 trial (LEAN study) showed subjects had reduction in weight, fasting glucose, and BMI on liraglutide, a GLP-1 analogue. It also showed slowing of the progression of fibrosis and resolution of NASH on biopsy in 39% (compared to 9% in placebo) when taken once daily for 48 weeks. GLP-1 analogues are not currently recommended for the treatment of NAFLD or NASH as more studies are needed to fully elucidate these effects.

Renin-Angiotensin-Aldosterone Agents

The renin-angiotensin system may induce fibrosis in NAFLD and angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers (ARBs) can improve insulin sensitivity. These medications have been hypothesized to exhibit their effect on NAFLD in this manner. ARBs, in small studies, including one RCT, have shown improvement in histologic inflammation and fibrosis. Additional research is needed before these medications can be recommended for the treatment of NAFLD.

L-carnitine

In one small randomized controlled trial, L-carnitine was found to improve steatosis, NAFLD histologic activity score, and improve aminotransferase levels. There is insufficient evidence to recommend L-carnitine as a treatment for NAFLD currently.

Probiotics

Pilot studies based on the theory that NAFLD may be linked to small intestine bacterial overgrowth have shown some promise with the use of probiotics and prebiotics but further studies are needed.

Future Medical Therapies

New medications are being developed for the treatment of NAFLD. Novel agents include tropifexor, an agonist of farnesoid X receptors used in combination with cenicriviroc, a CCR2 and CCR5 receptor inhibitor, elafibranor, an investigational dual PPAR-gamma and -alpha agonist, selonsertib, an inhibitor of apoptosis signal-regulating kinase (ASK1), aramchol, a synthetic conjugate of fatty acid and bile acid conjugate (FABAC), emricasan, a pan-caspase inhibitor with anti-apoptotic and anti-inflammatory properties, and simtuzumab, a humanized monoclonal antibody against LOXL2 with anti-fibrotic properties.

Liver Transplantation

NASH cirrhosis is the second-most-common indication for liver transplantation in the United States, representing 21% of transplants. In those with decompensated NASH cirrhosis, liver transplantation should be considered. Comorbid conditions (e.g., morbid obesity, severe complications of diabetes, cardiac disease) may preclude transplantation candidacy in this group. Post-transplant outcomes for NASH cirrhosis are similar to other indications. Following transplant, most have persistent metabolic syndrome, with long-term implications but no effect on 5-year graft survival. Moreover, NAFLD has been shown to recur in the liver allograft, with a possible rapid progression to steatohepatitis and cirrhosis.

Summary

Summary

  • Nonalcoholic fatty liver disease (NAFLD), a condition associated with obesity and diabetes, is increasingly being recognized in the Western population.
  • Simple steatosis is the most common form of NAFLD and seems to be a benign condition. In contrast, nonalcoholic steatohepatitis (NASH) can progress to advanced fibrosis and cirrhosis.
  • The diagnosis is often made after an incidental finding of elevated liver enzyme levels or due to the clinician’s suspicion regarding a patient with obesity or diabetes. Imaging modalities can evaluate the degree of steatosis and fibrosis non-invasively, however, only liver biopsy can differentiate simple steatosis from NASH.
  • Current practice guidelines recommend multi-modal weight loss through diet and exercise, and pioglitazone and vitamin E in eligible patient groups. Other therapies require further investigation before they can be recommended.

Table 7. Treatment Summary for NAFLD

  Guideline Recommended Guideline Conditional Insufficient Data to Recommend Not Recommended
Mediterranean diet All patients      
Weight loss All patients      
Weight loss medications           ✓
Bariatric surgery   Morbidly obese patients (BMI ≥40 or ≥35 with comorbidity), not specifically for NASH, no specific method of bariatric surgery recommended over another    
Exercise All patients      
Coffee         ✓  
Statins   Dyslipidemic patients      
Fibrates   Dyslipidemic patients    
Omega-3 fatty acids         ✓  
vitamin E 800IU/day   Non-diabetics with biopsy-proven NASH, men without history of prostate cancer, after discussion or risks and benefits    
pioglitazone   Diabetics and non-diabetics with NASH    
metformin           ✓
Probiotics         ✓  
Angiotensin-II receptor blockers         ✓  
ursodeoxycholic acid           ✓
obeticholic acid         ✓  
L-carnitine         ✓  
pentoxifylline         ✓  
liraglutide         ✓  
Suggested Reading

Suggested Reading

  • Angulo P: Nonalcoholic fatty liver disease. N Engl J Med 2002; 346:1221-1231.
  • Mc Cullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin Liver Dis. 2004 Aug;8(3):521-33, viii.
  • Younossi ZM, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011;9:524-530.e521.
  • Williams CD, Stengel J, Asike MI et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy. Gastroenterol 2011; 140: 124-131.
  • Torres DM, Harrisson SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterol 2008; 134:1682-1998.
  • Ramesh S & Sanyal A. Evaluation and management of non-alcoholic steatohepatitis. J Hepatol 2005; 42(Suppl 1):S2-S12.
  • Eddowes PJ, Sasso M, Allison M, et al. Accuracy of FibroScan Controlled Attenuation Parameter and Liver Stiffness Measurement in Assessing Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 2019 May;156(6):1717-1730. doi: 10.1053/j.gastro.2019.01.042. Epub 2019 Jan 25.
  • Della Corte C, Alisi A, Iorio R, et al. Expert opinion on current therapies for nonalcoholic fatty liver disease. Expert Opin Pharmacother 2011; 12:1901-1911.
  • Pent L, Wang J, Li F. Weight reduction for non-alcoholic fatty liver disease. Cochrane Database Syst Rev 2011; 15: CD003619.
  • Sanyal AJ, Chalasani MB, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362:1675- 1685.
  • Musso G, Gambino R, Cassader M, Paganu G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 2010; 52:79-104.
  • Brunt EM, Wong VW, Nobili V, et al. Nonalcoholic fatty liver disease. Nat Rev Dis Primers. 2015;1:15080
  • Thomas C, Day CP, Tenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol 2012 Jan;56(1):255-66. Epub 2011 Jul 1.
  • Ryan MC, Isiopoulos C, Thodis T, et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol 2013;59:138-143.
  • Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006 Nov 30;355(22):2297-307.
  • Chalasani N, Younossi Z, Lavineet J, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guideline from the American Association for the Study of Liver Diseases. Hepatology 2018 Jan;67(1):328-357. Epub 2017 Sep 29.
  • European Association for the Study of the Liver, European Association for the Study of Diabetes, and European Study for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Journal of Hepatology 2016. Volume 64, Issue 6, 1388-1402.
  • Mitchell T, Jeffrey GP, Boer B, et al. Type and Pattern of Alcohol Consumption is Associated with Liver Fibrosis in Patients With Non-alcoholic Fatty Liver Disease. Am J Gastroenterol 2018 Oct;113(10):1484-1493.
  • Aberg F, Helenius-Hietala J, Puukka P, Farkkila M, and Jula A. Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population. Hepatology 2018 Jun;67(6):2141-2149. Epub 2018 Apr 16.
  • Hajifathalian K, Torabi Sagvand B, McCullough AJ. Effect of Alcohol Consumption on Survival in Nonalcoholic Fatty Liver Disease: A National Prospective Cohort Study. Hepatology 2019 Aug;70(2):511-521. Epub 2018 Oct 2.
  • Weng G and Dunn W. Effect of alcohol consumption on nonalcoholic fatty liver disease. Transl Gastroenterol Hepatol 2019; 4:70. Published online 2019 Sep 17.
  • Hyogo H, Ikegami T, Tokushige K, et al. Efficacy of pitavastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia: An open-label, pilot study. Hepatol Res 2011 Nov;41(11):1057-65. Epub 2011 Sep 22.
  • Nakahara T, Hyogo H, Kimura Y, et al. Efficacy of rosuvastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia: An open-label, pilot study. Hepatol Res. 2012 Nov;42(11):1065-72. doi: 10.1111/j.1872-034X.2012.01034.x. Epub 2012 May 14.
  • Kargiotis K, Athyros VG, Giouleme O, et al. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome. World J Gastroenterol. 2015 Jul 7;21(25):7860-8. doi: 10.3748/wjg.v21.i25.7860.
  • Younossi ZM et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: Interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2019 Dec 5; 394:2184.