Epidemiology of Nonalcoholic Fatty Liver Disease and... : Transplantation (original) (raw)

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of chronic liver disease. In fact, NAFLD is now among the top indications for LT in United States and is rapidly growing in the rest of the world.1 Therefore, a number of epidemiologic issues related to NAFLD must be considered in the context of the clinical considerations for LT.

First, it is important to understand that NAFLD is a spectrum of clinicopathologic diseases that include nonalcoholic fatty liver (NAFL or simple steatosis), nonalcoholic steatohepatitis (NASH), cirrhosis, and its complications.1 Second, the diagnosis of NAFLD requires the absence of secondary causes of fatty liver such as excessive alcohol use. The definition of excessive alcohol use has changed over time but the most recent studies of NAFLD defined it as greater than 20 g/d in men and greater than 10 g/d for women.2 Furthermore, other causes of fatty liver, such as steatogenic medications, or hereditary disorders, such as Wilson disease or lipodystrophy, must be excluded.2 Third, NASH is the subtype of NAFLD that is histologically defined by presence of hepatic steatosis, lobular inflammation, and hepatocellular ballooning or other evidence of hepatocyte injury, including pericellular fibrosis.1 These histologic changes are similar to those of alcoholic steatohepatitis (ASH) in the absence of excessive alcohol use and both have the potential to progress to cirrhosis and its complications.3 Fourth, the progression of liver disease in NASH is not linear and can be manifested by periods of progression, regression and stability. Exactly how long an individual with NASH spends in these states and what factors are associated with disease progression and regression have not been clearly elucidated. The following sections summarize evidence related to our current knowledge about the epidemiology and impact of NAFLD and NASH as they relate to liver transplantation.1–7

Prevalence and Incidence

For the past 2 decades, there has been increasing evidence supporting a very high prevalence of NAFLD and NASH in the general population. In a recent meta-analysis, the global prevalence of NAFLD was estimated to be 25.2% with the highest prevalence in the Middle East and South America (31.8% and 30.4%, respectively) and the lowest rates reported from Africa (13.5%). Additionally, the prevalence rates for NAFLD in North America, Europe, and Asia were reported to be 24.1%, 23.7%, and 27.4%, respectively (Figure 1).4 Furthermore, the prevalence of NASH in the general population is estimated to be between 1.5% and 6.45%.4 These high prevalence rates for NAFLD and NASH are being driven by the global epidemic of diabetes and obesity.1,2 Considering the continuing increase in diabetes and obesity, the future burden of NAFLD in the United States is estimated to increase substantially. A recent modeling study estimated that the prevalence of NASH in the United States will increase 63% by 2030, leading to an increasing incidence of NASH-related decompensated cirrhosis by 168%, hepatocellular carcinoma (HCC) by 137%, liver-related deaths by 178%, and causing approximately 800 000 excess liver deaths.5

F1

FIGURE 1:

Global prevalence of NAFLD.

Although the prevalence of NAFLD and NASH is quite high in the general population, they are even higher in specific cohorts, such as those with type 2 diabetes mellitus (T2DM) and the morbidly obese. In a systematic review of studies including 222 816 patients with diabetes from 25 countries, the overall global prevalence of NAFLD among patients with T2DM was 61.1%.6 Furthermore, the prevalence of NASH among biopsied diabetes can be as high as 64.0%, whereas the prevalence of advanced fibrosis (fibrosis, ≥ F3) in patients with T2DM can be around 10.4%.6,8 As noted previously, NAFLD is closely linked to obesity. The prevalence of NAFLD has been shown to increase with increasing body mass index (BMI),8 and among morbidly obese individuals who undergo weight reduction surgery, the prevalence of NAFLD has been estimated to be over 95%.9 Also, the presence of metabolic syndrome, mixed hyperlipidemia, and hypocholesterolemia due to familial hypobetalipoproteinemia are also reported to be significant metabolic risk factors for NAFLD.9

In addition to these metabolic risk factors, age, sex, and ethnicity can also have a major influence on the risk of NAFLD. In fact, NAFLD prevalence is higher in the older patients and this prevalence rate increases with age, male sex, and Hispanic ethnicity.9

Despite the close association of NAFLD with obesity, there is increasing recognition that there is a subgroup of patients with NAFLD who are not obese.10-16 In the United States, 5% to 10% of patients with NAFLD are considered “lean” according to their BMI.10 The nonobese NAFLD group appears to be less metabolically abnormal than obese NAFLD but more metabolically abnormal than the lean subjects without NAFLD.10,11 In addition to the data from the United States, data from Europe suggest that the prevalence of lean NAFLD in the biopsy-proven NAFLD cohort is about 20%,13,14 whereas the prevalence of lean NAFLD in Asia is reported to range from 19% to 23%.15,16 It is likely that both lean and obese NAFLD share a common altered metabolic profile with an excess of abdominal adipose tissue and an increased prevalence of comorbidities, such as T2DM and hypertension.1,2 The exact contribution of one's genetic background and the exposure to certain environmental factors in promoting development of NAFLD among lean individuals has not been entirely clarified.1

Long-term Outcomes of Patients With NAFLD and NASH

Evidence for the natural history of NAFLD comes from 2 types of studies. The first type of study relies on liver biopsies to establish the diagnosis of NASH. The second type of study relies on imaging and other noninvasive biomarkers to determine the presence NAFLD and its natural history.

Histology-based studies have provided evidence that, in general, there is a differential risk of progression for different subtypes of NAFLD.1,2,12,17-19 The initial studies suggested that patients with histologically proven NASH are at the highest risk for progressive liver disease and cirrhosis.17-19 In fact, a study from the United States, which included 289 NAFLD patients with liver biopsies and long-term data, reported that more than half of the NAFLD cohort had histologic NASH. NASH patients were predominantly female, had higher AST, ALT, and higher fasting serum glucose levels. After 12 years of follow-up, patients with NASH had a 6 times higher risk of liver-related mortality than non-NASH NAFLD patients.20 These data have been substantiated by multiple other studies which have documented the increased risk of progression in patients with NASH.1,2,17-19

Nevertheless, it is possible that a small number of NAFLD patients without NASH can develop NASH overtime and progress.1,2 The exact circumstances under which these patients can progress has not been fully described. It is important to note that the histologic stage of hepatic fibrosis in patients with NASH has been repeatedly shown to be the most important predictor of liver-related and possibly all-cause mortality.21-23

Even in the context of histologic subtypes of NAFLD, there is a clear impact of the components of metabolic syndrome on accelerating the outcomes of patients with NAFLD.11,21-25 In cross-sectional studies, the presence of T2DM is independently associated with moderate to severe hepatic fibrosis.21

The second type of study used population-based databases to assess the long-term outcomes of patients with NAFLD. In most of these population-based studies, NAFLD was diagnosed radiologically or with noninvasive biomarkers such as Fatty Liver Index (FLI).1,2 Most of these studies have suggested an increased mortality in patients with NAFLD.4 Additionally, these studies have also provided evidence that the metabolic clinical profile of patients with NAFLD may accelerate disease progression.

In an analysis using data from NHANES and the National Death Index data set, the presence of diabetes doubled the risk of overall and liver-related mortality in patients with NAFLD.24 In addition to the clinically overt influence of T2DM, a diagnosis of metabolic syndrome has also been shown to increase the risk of liver-related mortality by 12 times.24 These results were confirmed in another study using NHANES III-National Death Index linked files where all-cause mortality, cardiovascular mortality, and liver-related mortality were all significantly higher in NAFLD patients with metabolic syndrome.11 Finally, another recent report using NHANES suggested that the number of metabolic syndrome components present accordingly increased the risk of NAFLD-related mortality.25

Despite the understanding of NAFLD from the long-term population-based data, the use of population-based data to study the long-term outcomes of patients with NASH is not feasible due to the histologic requirements for diagnosing NASH. Nevertheless, using surrogate markers of NASH from a population-based data set, a 2.5-fold increase in the prevalence of NASH-related cirrhosis over 2 decades was found.26

Finally, data from sequential biopsies of patients with NASH suggest that the progression is not linear Although some NASH patients show progression of fibrosis, others have fibrosis regression or remain stable, Although factors associated with progression seem to be similar to those reported by clinical research, factors associated with regression of fibrosis are not clear.7 In addition, those with NASH are at an increased risk for liver-related mortality. However, in all patients with NAFLD or NASH, the most common cause of death is from cardiovascular causes. Current evidence suggests that between 5% and 10% of NAFLD patients die from cardiovascular disease.27

Although all patients with NAFLD and NASH are at risk for cardiovascular disease, patients with advanced fibrosis have been shown to have 2 to 3 times higher risk of cardiovascular mortality.27,28 Despite this tight association, the exact link of NAFLD and cardiovascular disease is still being debated. Nevertheless, one proposal suggests a commonly shared pathogenic pathway created by a proinflammatory environment perpetuated by obesity and diabetes.29 Furthermore, there is mounting evidence that endothelial dysfunction in patients with NAFLD may play an important role in the pathogenesis of cardiovascular diseases in patients with NAFLD.29

Patients with NAFLD and NASH are also at risk for developing HCC.2 In fact, patients with NAFLD fibrosis stages 3 and 4 have been shown to have an approximately 7 times higher risk for developing HCC than those without liver disease.30 It is interesting to note that there is mounting evidence suggesting that some patients with NAFLD may develop HCC in the absence of significant hepatic fibrosis. Although intriguing, the extent of this contribution of NAFLD patients without cirrhosis to the burden of HCC has not been clearly defined.30 Nevertheless, given the enormous number of patients with NAFLD and NASH, patients NASH-related HCC is increasingly being seen in the clinical setting. One indirect evidence supporting this fact is the number of patients being listed for LT related to HCC. In fact, a recent study from the United States assessed the changes in the listing and outcomes of patients with HCC who were listed for LT31 The data clearly showed that NASH-related HCC is the most rapidly growing HCC indication for LT in the United States and is poised to become the most common indication for liver transplant in the near future.31,32 Furthermore, these patients experienced good outcomes while being listed for LT and in the posttransplant setting.33 In addition to NASH-related HCC, there is substantial evidence that NASH-related advanced liver disease or cirrhosis is also rapidly becoming a major indication for LT in the United States.33,34

In summary, the epidemiologic data over the last 2 decades have demonstrated that NAFLD is rapidly becoming a very common type of liver disease associated with cirrhosis and HCC as well as an indication for LT. The data also suggest that NAFLD is strongly associated with T2DM and obesity in which patients who have these comorbidities are at a higher risk for adverse outcomes, such as cirrhosis, HCC, and mortality. These data are also crucial to develop management strategies to target the population at the highest risk for adverse outcomes in NAFLD. Additionally, these data can inform the transplant team about NAFLD patients who are increasingly becoming transplant candidates and the issues that must be considered in this patient population.

The Extrahepatic Manifestations of NAFLD/NASH and Their Impact on LT

As noted previously, NAFLD is highly associated with metabolic syndrome and each component of metabolic syndrome increases the risk of NAFLD and its adverse outcomes.4,32,33,35-39 In fact, a meta-analysis of NAFLD patients on the waiting list for LT confirmed the high prevalence of metabolic comorbidities in these patients (obesity, 53.4%-68%; T2DM, 49%-72.9%; arterial hypertension, 37.5%-75%).32

As noted previously, there is high prevalence of cardiovascular diseases (coronary artery disease, 20%; congestive heart failure, 7%; stroke, 8%)36 and sarcopenia (about 45%)37 in patients transplanted for NASH. Furthermore, these high rates of metabolic comorbidities may create barriers for being listed for LT.31,33,35 Pretransplant and posttransplant diabetes has been found to be associated with higher complications including higher mortality.40

In addition, the presence of morbid obesity (BMI ≥ 40 kg/m2) may cause some technical challenges, increase the pretransplant length of stay in intensive care unit,38 and is associated with posttransplant complications.39 However, the impact of morbid obesity on long-term mortality after LT has been debated. One study of 25 647 patients listed for LT found that neither undernutrition (BMI, < 20) nor morbid obesity had a significant impact on mortality,41 whereas another study demonstrated that patients with morbid obesity at baseline experienced a significantly higher 5-year mortality rate due to cardiovascular-related deaths.42 Furthermore, another study confirmed that the morbidly obese patients had a higher number of infectious complications to include cellulitis and pneumonia possibly due to the higher prevalence of T2DM in this population, as well as cancer events, which increased mortality.43

Finally, emerging data suggest that the presence of sarcopenia is also associated with higher mortality during transplant waitlisting44 as well as increased hospitalization and length of stay in the posttransplant setting.45 Finally, the available data have also shown that the persistence of sarcopenia after LT is associated with increased mortality.37

Interaction of Alcoholic Liver Disease and NAFLD: The Impact on the Outcomes and LT

As noted previously, steatohepatitis can be associated with excessive alcohol consumption with or without metabolic risk factors. Using an arbitrary threshold, NASH has been defined by the absence of alcohol consumption greater than 20 to 30 g/d in men and greater than 10 to 20 g/d in women.2,46 However, it is increasingly recognized that many patients with alcohol consumption above this cutoff also have metabolic risk factors that probably contribute to disease progression as much as excessive alcohol consumption.

The frequency of overlap of NASH and ASH in patients who are considered for LT is impossible to evaluate because there are no codes in the LT registries to determine this overlap. This group of patients is probably included in the group of alcoholic liver disease with metabolic risk factors. It is also possible that some patients who are diagnosed as NAFLD are associated with an underestimation of the deleterious effects of alcohol consumption.

The coexistence of excessive alcohol consumption and metabolic risk factors was recently found to markedly increase the risk of severe liver disease, even when alcohol consumption was within the cutoff for NAFLD/NASH.47 Also, the effect of metabolic risk factors and alcohol seem to have an effect that is more synergistic rather than additive.48,49 Furthermore, from an epidemiological study in Pomerania, there is evidence of a significant overlap of both risk factors in the general population.50 In this context, it is well known that NASH and ASH have significantly increased in parallel over the last decade.33,34,51 In a recent study of general population from the United States, there was significant overlap between ASH and NASH.52 Furthermore, the presence of metabolic syndrome was the only independent predictor of mortality in those who drunk excessively.52 These data suggest that the impact of alcohol on the liver is exacerbated by the presence of metabolic abnormalities.

How Can NAFLD/NASH Be Prevented in the General Population?

As noted previously, diabetes and obesity are the main factors driving the prevalence of NAFLD in the general population.53 The worldwide prevalence of obesity is rising almost everywhere; more than 1 in 2 adults and nearly 1 in 6 children are overweight or obese, in keeping with a steady increase in the estimated obesity rates until at least 2030.54 Similarly, the numbers for diabetes are gloomy; obesity accounts for diabetes epidemics (current estimate, 425 million worldwide), with projections for 2045 totaling around 630 million,55 with 75% of them living in urban areas (urban diabetes).

Longitudinal analyses of large cohorts indicate that obesity in childhood56 and in early adulthood57 is associated with an increased risk of mortality from liver-related causes, confirming a NAFLD-mediated pathway of advanced liver disease.58 Whereas lifestyle changes aimed at healthy diet and habitual physical activity may be implemented in individual patients at risk of progressive NAFLD,59 prevention in the general community depends on global health policies. The global health policies need to include pricing and fiscal measures, school-based, worksite and primary care interventions, food industry, and transport policies.60,61 There is also evidence suggesting that nutrition labeling enables consumers to make healthier food choices, in particular “traffic light labeling” that was quoted by the World Health Organization as a good measure to tackle obesity.62 The final target is to increase awareness in the community, to empower consumers, and to regulate marketing of potentially unhealthy products.

SUMMARY AND RECOMMENDATIONS

  1. Considering the large heterogeneity of the data derived from population studies, the evaluation of risk of liver disease progression should be determined based on the ethnic origin and sex (grade of evidence, B; grading of recommendation, 1).
  2. In the overall assessment of risk, fibrosis is the most relevant risk factor for predicting mortality and should be accurately determined by liver biopsy and eventually by validated surrogate markers including serum based biomarkers and imaging tests (grade of evidence, B; grading of recommendation, 1).
  3. Clinically, patients with NAFLD with multiple components of metabolic syndrome are at increased risk for overall, cardiovascular, and liver-related mortality. We recommend that individuals who present with features of metabolic syndrome in the presence of elevated liver enzymes should be screened (grade of evidence, A; grading of recommendation, 1).
  4. Although the presence of NAFLD increases the risk for liver-related mortality, cardiovascular disease is the most common cause of death in patients with NAFLD and NASH. We recommend that NAFLD patients, especially those with multiple cardiovascular risks, should be screened for cardiovascular diseases and managed according to the findings (grade of evidence, A; grading of recommendation, 1).
  5. Comorbidities in NAFLD/NASH patients, who are considered for LT, are important to be assessed in the pretransplant and posttransplant settings because these factors affect waitlist mortality, resource utilization, as well as leading to increased posttransplant complications, morbidity and perhaps mortality (grade of evidence, C; grading of recommendation, 1).
  6. Currently, no formal recommendation can be made regarding the frequency of the indication for LT in the overlapping group of patients with NASH and ASH, or whether these indications are different from that for NASH or ASH alone. However, there is evidence that both conditions are increasing in parallel and have a synergistic effect, thus suggesting that the frequency of this association is increasing (grade of evidence, C; grading of recommendation, 3).
  7. Any attempt to decrease the incidence of NAFLD should ideally address obesity starting from childhood and early adulthood, favoring the adoption of healthy lifestyles through a comprehensive health policy (grade of evidence, IA; grading of recommendation, 1).

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