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Medicines 6 (1): 41 (2019)
Iqbal, Umair
Perumpail, Brandon J.
Akhtar, Daud
Kim, Donghee
Ahmed, Aijaz
Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver damage from the more prevalent (75%–80%) and nonprogressive nonalcoholic fatty liver (NAFL) category to its less common and more ominous subset, nonalcoholic steatohepatitis (NASH). NAFLD is now the most common cause of chronic liver disease in the developed world and is a leading indication for liver transplantation in United States (US). The global prevalence of NAFLD is estimated to be 25%, with the lowest prevalence in Africa (13.5%) and highest in the Middle East (31.8%) and South America (30.4%). The increasing incidence of NAFLD has been associated with the global obesity epidemic and manifestation of metabolic complications, including hypertension, diabetes, and dyslipidemia. The rapidly rising healthcare and economic burdens of NAFLD warrant institution of preventative and treatment measures in the high-risk sub-populations in an effort to reduce the morbidity and mortality associated with NAFLD. Genetic, demographic, clinical, and environmental factors may play a role in the pathogenesis of NAFLD. While NAFLD has been linked with various genetic variants, including PNPLA-3, TM6SF2, and FDFT1, environmental factors may predispose individuals to NAFLD as well. NAFLD is more common in older age groups and in men. With regards to ethnicity, in the US, Hispanics have the highest prevalence of NAFLD, followed by Caucasians and then African-Americans. NAFLD is frequently associated with the components of metabolic syndrome, such as type 2 diabetes mellitus (T2DM), obesity, hypertension, and dyslipidemia. Several studies have shown that the adoption of a healthy lifestyle, weight loss, and pro-active management of individual components of metabolic syndrome can help to prevent, retard or reverse NAFLD-related liver damage. Independently, NAFLD increases the risk of premature cardiovascular disease and associated mortality. For this reason, a case can be made for screening of NAFLD to facilitate early diagnosis and to prevent the hepatic and extra-hepatic complications in high risk sub-populations with morbid obesity, diabetes, and other metabolic risk factors.
medicinesReviewThe Epidemiology, Risk Profiling and DiagnosticChallenges of Nonalcoholic Fatty Liver DiseaseUmair Iqbal 1,*, Brandon J. Perumpail 2, Daud Akhtar 3, Donghee Kim 4 and Aijaz Ahmed 41 Department of Medicine, Geisinger Commonwealth School of Medicine, Danville, PA 17822, USA2 Department of Medicine, Drexel University College of Medicine, Philadelphia, PA 19129, USA;brandonperumpail@gmail.com3 Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada;dakhtar@alumni.ubc.ca4 Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305,USA; dhkimmd@stanford.edu (D.K.); aijazahmed@stanford.edu (A.A.)* Correspondence: uiqbal@geisinger.edu or umairiqbal_dmc@hotmail.comReceived: 18 February 2019; Accepted: 9 March 2019; Published: 18 March 2019Abstract: Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver damagefrom the more prevalent (75%–80%) and nonprogressive nonalcoholic fatty liver (NAFL) categoryto its less common and more ominous subset, nonalcoholic steatohepatitis (NASH). NAFLD is nowthe most common cause of chronic liver disease in the developed world and is a leading indicationfor liver transplantation in United States (US). The global prevalence of NAFLD is estimated tobe 25%, with the lowest prevalence in Africa (13.5%) and highest in the Middle East (31.8%) andSouth America (30.4%). The increasing incidence of NAFLD has been associated with the globalobesity epidemic and manifestation of metabolic complications, including hypertension, diabetes,and dyslipidemia. The rapidly rising healthcare and economic burdens of NAFLD warrant institutionof preventative and treatment measures in the high-risk sub-populations in an effort to reduce themorbidity and mortality associated with NAFLD. Genetic, demographic, clinical, and environmentalfactors may play a role in the pathogenesis of NAFLD. While NAFLD has been linked with variousgenetic variants, including PNPLA-3, TM6SF2, and FDFT1, environmental factors may predisposeindividuals to NAFLD as well. NAFLD is more common in older age groups and in men. With regardsto ethnicity, in the US, Hispanics have the highest prevalence of NAFLD, followed by Caucasiansand then African-Americans. NAFLD is frequently associated with the components of metabolicsyndrome, such as type 2 diabetes mellitus (T2DM), obesity, hypertension, and dyslipidemia. Severalstudies have shown that the adoption of a healthy lifestyle, weight loss, and pro-active management ofindividual components of metabolic syndrome can help to prevent, retard or reverse NAFLD-relatedliver damage. Independently, NAFLD increases the risk of premature cardiovascular disease andassociated mortality. For this reason, a case can be made for screening of NAFLD to facilitate earlydiagnosis and to prevent the hepatic and extra-hepatic complications in high risk sub-populationswith morbid obesity, diabetes, and other metabolic risk factors.Keywords: nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; NAFLD; NASH; liver biopsy1. IntroductionNonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseasein the developed world and is one of the leading indications for liver transplantation in the UnitedStates (US) [1,2]. Over 64 million people in the US are estimated to have NAFLD, with annual medicalcosts of approximately $103 billion (1612.18 per patient) [3]. NAFLD comprises nonalcoholic fattyMedicines 2019, 6, 41; doi:10.3390/medicines6010041 www.mdpi.com/journal/medicinesMedicines 2019, 6, 41 2 of 19liver (NAFL), which is characterized by the presence of hepatic steatosis without the presence of anysubstantial inflammation, and nonalcoholic steatohepatitis (NASH), which is defined by the histologicpresence of hepatic steatosis with lobular inflammation, and hepatocellular balloon degeneration withand without pericellular fibrosis [3]. The components of metabolic syndrome have been associatedwith the pathogenesis of NAFLD. These include risk factors such as obesity, diabetes, hypertension,and dyslipidemia [2]. Additionally, the pathogenesis of NAFLD also comprises genetic, demographic,clinical, and environmental factors that all play a role in determining the likelihood of NAFLD. Despitethe NAFLD epidemic in chronic liver disease, direct treatment options are still lacking and thus addto the economic burden on healthcare systems [3]. For this reason, there is a need to identify the riskfactors associated with NAFLD to effectively screen patients. The purpose of this article is to discussthe epidemiologic trends, risk factors, and the current modalities involved in the diagnostic evaluationof NAFLD.2. Epidemiology of NAFLD2.1. Prevalence and Distribution of NAFLDThe worldwide increase in the prevalence of well-established risk factors for NAFLD, such asdiabetes, obesity, and age, has had an accompanying increase in the prevalence of NAFLD. The globalprevalence of NAFLD is estimated to be around 25% [4]. In a recent meta-analysis, NAFLD was foundto be most prevalent in the Middle East (31.8%), followed by South America (30.4%). NAFLD wasalso found to be least prevalent in Africa (13.5%) [4]. Comparatively, the prevalence of NAFLD inAsia, Europe, and North America was found to be 27.4%, 23.7%, and 24.1% respectively [4]. Figure 1summarizes the prevalence of NAFLD across the world. The US population has seen a similar trendwith the National Health and Nutrition Examination Survey (NHANES), demonstrating a doubling inthe prevalence of NAFLD in the US from 5.5% (1988–1994) to 11% (2005–2008) [1]. In a study using thefatty liver index to diagnose NAFLD, the prevalence of NAFLD increased from 18% in 1988–1991 to31% in 2011–2012 [5]. Concerningly, the prevalence of NASH in the general population is estimated torange between 1.5% and 6.4% [4]. This increasing prevalence of NAFLD in the US parallels the increasein prevalence of NAFLD-related risk factors, which include insulin resistance, obesity, hypertension,and dyslipidemia.edicines 2019, 6, x FOR PEER REVIEW 2 of 19 of approximately $103 billion (1612.18 per patient) [3]. NAFLD comprises nonalcoholic fatty liver (NAFL), which is characterized by the presence of hepatic steatosis without the presence of any substantial inflammation, and nonalcoholic steatohepatitis (NASH), which is defined by the histologic presence of hepatic steatosis with lobular inflammation, and hepatocellular balloon degeneration with and without pericellular fibrosis [3]. The components of metabolic syndrome have been associated with the pathogenesis of NAFLD. These include risk factors such as obesity, diabetes, hypertension, and dyslipidemia [2]. Additionally, the pathogenesis of NAFLD also comprises genetic, demographic, clinical, and environmental factors that all play a role in determining the likelihood of NAFLD. Despite the NAFLD epidemic in chronic liver disease, direct treatment options are still lacking and thus add to the economic burden on healthcare systems [3]. For this reason, there is a need to identify the risk factors associated with NAFLD to effectively screen patients. The purpose of this article is to discuss the epidemiologic trends, risk factors, and the current modalities involved in the diagnostic evaluation of NAFLD. 2. Epidemiology of NAFLD 2.1. Prevalence and Distribution of NAFLD The worldwide increase in the prevalence of well-established risk factors for NAFLD, such as diabetes, obesity, and age, has had an accompanying increase in the prevalence of NAFLD. The global prevalence of NAFLD is estimated to be around 25% [4]. In a recent meta-analysis, NAFLD was found to be most prevalent in the Middle East (31.8%), followed by South America (30.4%). NAFLD was also found to be least prevalent in Africa (13.5%) [4]. Comparatively, the prevalence of NAFLD in Asia, Europe, and North America was found to be 27.4%, 23.7%, and 24.1% respectively [4]. Figure 1 summarizes the prevalence of NAFLD across the world. The US population has seen a similar trend with the National Health and Nutrition Examination Survey (NHANES), demonstrating a doubling in the prevalence of NAFLD in the US from 5.5% (1988–1994) to 11% (2005–2008) [1]. In a study using the fatty liver index to diagnose NAFLD, the prevalence of NAFLD increased from 18% in 1988–1991 to 31% in 2011–2012 [5]. Concerningly, the prevalence of NASH in the general population is estimated to range between 1.5% and 6.4% [4]. This increasing prevalence of NAFLD in the US parallels the increase in prevalence of NAFLD-related risk factors, which include insulin resistance, obesity, hypertension, and dyslipidemia. Figure 1. Prevalence of nonalcoholic fatty liver disease (NAFLD) across the world [4]. 2.2. Populations with NAFLD Figure 1. Prevalence of nonalcoholic fatty liver disease (NAFLD) across the world [4].Medicines 2019, 6, 41 3 of 192.2. Populations with NAFLDDiabetes and obesity, in particular, are significant health concerns that are heavily associated withNAFLD. A recent systematic review estimated the global prevalence of NAFLD in diabetic patients tobe around 58% [6]. Specifically, the prevalence of NASH in diabetic patients has been demonstratedto be close to 65% [6,7]. Furthermore, NAFLD is also highly prevalent in the overweight and obesepopulation. The prevalence of NAFLD in morbidly obese patients who undergo bariatric surgeryhas been reported to be as high as 95% [8]. Although there is a strong association between NAFLDand excess body weight, NAFLD can also present in patients with a normal body mass index (BMI).Approximately 5–10% of NAFLD patients in the US are within the normal limits for BMI and arecommonly referred to as having lean NAFLD [9]. The pathogenesis of lean NAFLD is analogous to thatof obese NAFLD and is similarly accompanied by excessive abdominal fat, diabetes, and hypertension.Age is another important consideration with regard to NAFLD. NAFLD is more prevalent in olderpatients, with the majority of patients being diagnosed between 40 to 50 years of age. The risk ofNASH and fibrosis also increases with age. The prevalence of NAFLD also varies with gender andethnicity, with there being a greater prevalence in males and individuals of Hispanic descent [4].Yang et al. displayed that men are at a higher risk of severe fibrosis when compared to premenopausalfemales. The risk, however, is similar in post-menopausal females, suggesting that female hormonesmay have protective effects on hepatic fibrosis [10]. A remodeling study by Estes et al. estimatedthat the prevalence of NAFLD and NASH in the US will rise by 21% and 63%, respectively, with acorrelated increase of 178% in liver-related mortalities to an estimated 78,300 deaths by 2030. For thisreason, there is a critical need to identify and treat potentially modifiable risk factors in order to reducethe morbidity and mortality associated with this serious disease [11].3. Risk Profiling for NAFLD3.1. Genetic Predisposition to NAFLDAlthough obesity, metabolic syndrome, and insulin resistance are the most prevalent riskfactors that lead to the development of NAFLD, NAFLD varies substantially among subjects withcomparable lifestyles, environmental exposures, and metabolic abnormalities. This suggests that otherfactors do contribute to the pathogenesis of NAFLD, with genetic predisposition possibly being animportant factor. Several epidemiological, familial, and twin studies have shown possible familialpredispositions for NAFLD. Struben et al. demonstrated in a study of eighteen members the coexistenceof histologically proven NASH and cirrhosis among multiple generations of kindreds [12]. A familystudy of 157 individuals with familial combined hyperlipidemia revealed an increased prevalenceof fatty liver and elevated levels of ALT in both dyslipidemic patients and family members withnormal lipid levels [13]. Loomba et al. further revealed a strong association between serum GGTlevels, fatty liver, and beta-2-adrenergic receptors in identical twins [14]. NAFLD has been shownto cluster in families with certain genetic variants. These include TM6SF2, PNPLA3, NCAN, andPPP1R3B genes that increase the heritability of NAFLD to up to 27% [15–21]. One genetic variantlinked with NAFLD is a missense mutation [Ile148->Met148 (I148M)] in the Palatin-like phospholipasedomain-containing 3 gene (PNPLA3) [9]. PNPLA3 exerts a strong influence on hepatic fat accumulationin GG homozygous individuals, showing 73% more hepatic fat content when compared with CChomozygous individuals. These patients were also more susceptible to the development of moresevere histologic liver damage, with a 3.24-fold greater risk of higher necro-inflammatory scores and a3.2-fold greater risk of developing fibrosis [15]. These associations were maintained irrespective of thedegree of obesity or the presence of diabetes [16,17]. The single variant in the PNPLA3 gene (I148M)has been shown to occur with the greatest frequency in Hispanics, followed by non-Hispanic whites,and the least in African Americans [9]. This may explain the low prevalence of NAFLD in AfricanAmericans despite the higher prevalence of obesity and diabetes in this population [4]. A minorallele in transmembrane 5 superfamily member 2 (TM6SF2) was associated with magnetic resonanceMedicines 2019, 6, 41 4 of 19spectroscopy-measured hepatic triglyceride content from the Dallas Heart Study [20]. In addition,the minor allele of TM6SF2 was noted to increase the risk for hepatic fibrosis independent of age,obesity, diabetes, and PNPLA3 genotype [21]. Other genetic variants, such as Farnesyl diphosphatefarnesyl transferase I (FDFT1), Collage type XIII, alpha 1 (COL13A1), and neurocan (NCAN), whichhave been identified by genomewide scans, have also been implicated with increased susceptibility toNAFLD [19]. Table 1 summarizes these different genetic variants linked with NAFLD.Table 1. Genetic variants associated with NAFLD.Gene Effect on NAFLD/NASHPalatine like phospholipase domain containing 3(PNPLA-3) [15–17]Increased risk of hepatic steatosis, incidence of NASHand severity of fibrosisFarnesyl diphosphate farnesyl transferase I (FDFT1) [19] Increased severity of NAFLD activity scoreCollagen type XIII alpha 1 (COL13A1) [19] Increased severity of fibrosisNeurocan (NCAN) [19] Increased risk hepatic steatosisGlucokinase regulatory protein (GCKR) [19] Increased risk hepatic steatosisTransmembrane 5 superfamily member 2 (TM6SF2) [21] Increased risk for hepatic fibrosis3.2. Gender and Age-Related Risk for NAFLDGender and age are important considerations with regards to NAFLD. The prevalence of NAFLDand NASH is generally higher in men [22–25]. However, some studies have also reported a higherprevalence of NAFLD in women [26,27]. In men, NAFLD follows an “Inverted U-Shaped Curve”with the prevalence increasing from younger to middle-aged individuals and then decreasing aroundthe age of 50 [23–25]. The prevalence of NAFLD appears to be lower in premenopausal women andincreases significantly after the age of 50, ultimately, peaking in the 6th decade of life [23–25]. Yang etal. displayed that men are at a higher risk of severe fibrosis when compared to premenopausal women.The risk, however, is similar in post-menopausal women, suggesting that female hormones may haveprotective effects on hepatic fibrosis [10]. NAFLD is more prevalent with advanced age due to anincrease in the prevalence of NAFLD-related risk factors, such as metabolic syndrome, diabetes, andhypertension. The risk of fibrosis and NASH also increases with advancing age. A recent systematicreview demonstrated that advancing age was found to be an independent predictor of advancedfibrosis [28]. Advancing age also increases the extrahepatic manifestations of NAFLD and, thus, thereis an increased risk for morbidity and mortality in older populations. The effects of gender on theoutcomes of NAFLD is still unclear, although some studies have reported worse outcomes of NAFLDin men [29,30].3.3. Differences in NAFLD from Race/EthnicityDifferent ethnic groups display multiple differences with regards to NAFLD when pertaining toits prevalence, gender distribution, and genetic predisposition. Specifically, the prevalence of NAFLDand NASH varies in individuals with different ethnicities. Hispanics exhibit the greatest prevalence ofNAFLD, which is then followed by Caucasians [4,8]. Interestingly, African-Americans have the lowestprevalence of NAFLD despite having the highest prevalence of obesity and metabolic syndrome [8].Additionally, the prevalence of NASH is also less prevalent in African-American patients with NAFLDwhen compared to Hispanic patients. It should be noted, though, that the prevalence of advancedfibrosis did not differ [31]. Different ethnicities also display gender differences in the distribution ofNAFLD. NAFLD is more prevalent in Caucasian men when compared to Caucasian women. Thispattern is not seen in the Hispanic and African-American populations [32]. Certain genetic variants,such as the I148M variant of PNPLA3, also differ between ethnicities. I148M, which is stronglyassociated with hepatic fat content and NAFLD, is highly frequent in Hispanics (49%) in comparisonto non-Hispanic Caucasians (23%) and African-Americans (17%) [18]. Studies have also demonstratedMedicines 2019, 6, 41 5 of 19an increased prevalence of I148M in Indian Asians, which may explain the high prevalence of NAFLDin these populations [33]. The literature is still unclear regarding outcomes in NAFLD pertaining to theprogression of cirrhosis and mortality in these different ethnic groups. For this reason, more researchis warranted to further delineate the role of ethnicity and genetic predisposition in NAFLD-relatedoutcomes. Table 2 summarizes these nonmodifiable risk factors of NAFLD.Table 2. Nonmodifiable risk factors for NAFLD.Factor Association with NAFLD Risk of Progression to NASHAge [23–25,28] Increases prevalence with age Increase risk of progression to NASHGender [22–25] Increase prevalence in men UnclearEthnicity [8,18,31,33]Hispanics has the highestprevalence followed byCaucasians and African-AmericanAssociation is still uncertain.African-American has less prevalence ofNASH despite highest prevalenceof obesity.Familial predisposition [12,14] Family history of NAFLD mightincreases the risk Unclear3.4. Excessive Abdominal Adipose Tissue Deposition and ObesityObesity is a major modifiable risk factor for NAFLD, with over one third of the US populationstruggling with obesity and the remaining two thirds being overweight [34]. NAFLD is two timesmore prevalent in overweight individuals and four times more prevalent in the obese population.Weight gain is strongly associated with the development of NAFLD, with even a modest weight gaindemonstrating an increase in the risk of developing NAFLD [35,36]. Obesity also increases the riskof NASH, fibrosis, and hepatocellular carcinoma, but current data are conflicting with some studies,failing to show an association between obesity and the progression of fibrosis [37,38]. The distributionof adipose tissue is more clearly associated to NAFLD than the amount of adipose tissue as presentingevidence displays a strong link between visceral adiposity and NAFLD. Visceral adiposity is associatedwith insulin resistance and increased hepatic fat content. The release of pro-inflammatory andpro-fibrogenic mediators, such as tumor necrotic factor (TNF) and leptin by visceral fat tissue, mayplay a role in the increased risk of fibrosis. By contrast, subcutaneous adiposity is inversely related tohepatic fat content [39,40]. Asian populations depict a greater occurrence of visceral adipose tissue,which predisposes them to NAFLD at a lower body mass index (BMI) [41]. A recent meta-analysisrevealed that obesity (as per ethnic-specific BMI cutoff) could predict a worse long-term prognosis inpatients with NAFLD [42]. Although there is a strong association between NAFLD and obesity, thereis a growing number of patients with NAFLD that have a normal BMI and are referred to as havinglean NAFLD. Lean NAFLD comprises 5–10% of patients with NAFLD in the US [9]. The prevalence oflean NAFLD is higher in Europeans and Asians [43,44]. These patients share common risk factors withobese NAFLD, with the increased prevalence of risk factors, such as hypertension and type 2 diabetesmellitus (T2DM). Obesity also increases the risk for cardiovascular diseases. Therefore, efforts shouldbe made to adopt healthy lifestyles and weight loss in order to prevent the morbidity and mortalityassociated with NAFLD.3.5. Insulin Resistance and Diabetes as a Risk Factor for NALFDInsulin resistance plays a major role in the pathogenesis of NAFLD. Adipose tissue releasespro-inflammatory cytokines, which is associated with insulin resistance. There are severalother potential mechanisms of insulin resistance in NAFLD, which include increased lipogenesis,mitochondrial fatty acid oxidation, serum free fatty acids (FFA) levels, and adiponectin [45]. Patientswith NAFLD have higher levels of FFA and lower levels of serum adiponectin. There is also a potentialrole of intestinal microbiota in insulin resistance, as composition of intestinal microbiota is distinct inpatients with NAFLD patients compared to non-NAFLD patient population [45,46].Medicines 2019, 6, 41 6 of 19The prevalence of NAFLD is significantly higher in patients with T2DM and ranges from 30%to 70% in various population-based studies. Overweight and obese individuals with T2DM are at aneven higher risk for NAFLD. NAFLD has been reported to be as high as 76% and 56% in obese T2DMpatients and biopsy-proven NASH, respectively [47]. A recent systematic review estimated the overallglobal prevalence of NAFLD to be around 58% in T2DM patients [6]. Although a correlation existsbetween hepatic fat content and aminotransferase levels, most T2DM patients have normal serumaminotransferase levels despite having higher hepatic fat content. For this reason, T2DM can haveNASH and fibrosis with normal liver chemistries [48]. T2DM patients are also at a higher risk fordeveloping NASH and liver-related complications, including mortality related to cirrhosis [49,50].Adams et al. revealed a two-fold increased risk of all-cause mortality in T2DM patients [51]. A studyby Zoppini et al. revealed similar findings with a three- to five-fold higher mortality mostly relatedto NAFLD [52]. NAFLD is also associated with cardiovascular disease, which is highly prevalent inT2DM, and recent studies demonstrate that NAFLD patients may have a higher risk of developingmicrovascular complications of T2DM [53,54]. These findings suggest that screening for NAFLDshould be considered in T2DM, as the presence of NASH can influence the treatment choice of T2DM.Insulin sensitizers have shown to be beneficial in improving the metabolic derangements in patientswith NAFLD/NASH [55]. Multiple studies have shown the benefit of pioglitazone in improvingthe biochemical and histological parameters of NASH [56,57]. AASLD guidelines also recommendconsidering the use of pioglitazone in biopsy-proven NASH patients [58]. Liraglutide has also beenstudied in NASH patients, and early investigations show some benefits. This does require furtherresearch to prove its clinical efficacy in the treatment of NASH [59]. Although several studies have beendone on evaluating the efficacy of metformin on liver chemistries and histology, AASLD guidelines donot recommend the use of metformin in NASH, as it has not been shown to improve liver histology [58].3.6. DyslipidemiaLipotoxicity can occur secondary to the accumulation of fat content in non-adipose tissues and canoccur secondary to insulin resistance in patients with NAFLD. It plays a pivotal role in 5h3 progressionof a milder form of NAFLD to NASH, as patients with NAFLD have higher levels of triglycerides, FFAs,and other types of lipids, like bile acids, free cholesterol, lysophosphatidyl cholines, and ceramides [60].As described above, elevated levels of FFAs can also promote insulin resistance and increase the riskof NAFLD [45,60]. Hypertriglyceridemia (HTG) is also an independent predictor of NAFLD, andscreening for NAFLD should be considered in this patient population, especially in the context ofelevated liver enzymes [61,62]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is released byhepatocytes and inhibits the uptake of low-density lipoproteins (LDL). PCSK9 levels also increase withhepatic fat accumulation and are associated with a degree of steatosis [63].Risk factors for HTG are similar to those of NAFLD and include insulin resistance and sedentarylifestyle. HTG also increases the risk of cirrhosis [64]. Studies have also shown an association betweenNASH and elevated levels of non-HDL cholesterol, which also increases the risk of cardiovasculardiseases. Kantartzis et al., in a study of 16 patients with fatty liver and 24 control subjects, revealed thatfatty liver is significantly associated with lower levels of high density [65]. Similar results were reportedfrom the community-based Framingham Heart study, which revealed that patients with fatty liverhad a higher prevalence of HTG and low HDL levels [66]. Given the association of dyslipidemia withNAFLD, several anti-hyperlipidemic drugs have been studied and have been shown to be effective inimproving the histological features of NASH. Statins are the most studied drug and have been shown toprevent hepatic fibrosis. Additionally, statins also decrease the risk for cardiovascular diseases, whichare highly prevalent in NAFLD patients. A meta-analysis of 259,453 patient showed that statins candecrease the progression of hepatic fibrosis, prevent hepatic decompensation in cirrhosis, and reduceall-cause mortality in patients with chronic liver disease [67]. In addition, statins have been shown tohave anticancer properties and may prevent the development of hepatocellular carcinoma (HCC) [68].Medicines 2019, 6, 41 7 of 19Therefore, statins should be considered for primary or secondary prevention of cardiovascular diseases,reducing risk of cirrhosis and HCC in patients with NAFLD/NASH [69,70].3.7. Intestinal Microbiota and Oxidative StressAlteration in intestinal microbiota has been shown to play a role in the development of NAFLD.Patients with NAFLD have a higher prevalence of small intestinal bacterial overgrowth and elevatedlevels of tumor necrosis factor-alpha (TNF-alpha) [46,71]. A study performed on 57 patients withbiopsy-proven NASH revealed that abundance of bacteroides was an independent risk factor of NASH.One possible mechanism of injury induced by intestinal microbiota is by endotoxin production, whichincreases the risk of steatosis [63]. Rifaximin is a minimally absorbable antibiotic, which has beenshown to be effective in patients with NAFLD by improving liver enzymes and decreasing NAFLD fatscore. Further research is ongoing, studying the role of intestinal microbiota in the pathogenesis ofNAFLD [72]. Oxidative stress has also been shown to be a significant risk factor of NAFLD. Insulinresistance can result in hyperinsulinemia, which in turn can block the mitochondrial oxidation of fattyacids, which are then partially metabolized by the peroxisomes and microsomes, with the subsequentproduction of reactive oxidation species (ROS) and lipid peroxidation [73]. This production of ROS andlipid peroxidation can exhaust antioxidant enzymes and make hepatocytes susceptible to injury [74].Several clinical studies have shown elevated oxidative stress and lipid peroxidation in patients withNAFLD [73,74]. Therefore, antioxidants can play a therapeutic role in improving the metabolicparameters in patients with NAFLD. Vitamin E is a potent antioxidant which has been shown to beeffective in patients with NAFLD/NASH. In a randomized controlled trial of 247 patients, use ofvitamin E was associated with improvement in nonalcoholic steatohepatitis compared to placebo [57].3.8. Metabolic SyndromeThe definition of metabolic syndrome is controversial and includes risk factors for cardiovasculardiseases such as hypertension, insulin resistance, obesity, and dyslipidemia [4]. There is a strongassociation between NAFLD and the presence of metabolic syndrome. In a meta-analysis of 411patients, hypertension increased the risk of developing of hepatic fibrosis [38]. NAFLD has also beenshown to increase the risk of arterial hypertension. A prospective cohort study of 22,090 Korean menrevealed that the incidence of hypertension increases with the degree of NAFLD and also illustratedthat NAFLD is an independent predictor of hypertension [50,75]. Although studies have shownsome association between hypertension and NAFLD, the evidence is weaker when comparing theassociation of NAFLD with diabetes and obesity. Ultimately, the screening of NAFLD should still beconsidered in hypertensive patients due to the higher prevalence of NAFLD in this population. Table 3summarizes major modifiable risk factor associated with NAFLD.Medicines 2019, 6, 41 8 of 19Table 3. Modifiable risk factors for NAFLD.Factor Association withNAFLDRisk of Progression toNASH TreatmentObesity [34–42] Increase prevalence Increase risk Weight loss, Bariatric SurgeryInsulin resistance [45,46] Increase prevalence Increase riskLifestyle modificationsPioglitazone may improvehistological features of NASH.Limited evidence available onclinical utility of Glucagon likepeptide 1 antagonists (GLP-1)Hyperlipidemia [60–70] Increase prevalence Increase riskStatins have shown to improvehepatic fibrosis. It can alsoreduce cardiovascular mortalityIntestinal Microbiota andoxidative stress [71–74]Higher prevalence ofsmall intestinal bacterialovergrowth in NAFLD.Increase riskRifaximin has demonstratedbenefit but further research isneeded.Antioxidants likevitamin E have shown benefit inpatients with NAFLDMetabolic Syndrome[38,50,75] Increase prevalence Increase riskLifestyle modifications, statins,pioglitazone, weight loss.Although the components of metabolic syndrome, such as obesity, diabetes, and dyslipidemia,constitute the major risk factors associated with NAFLD, there are several other possible risk factorsdescribed in the literature. There is evidence which suggests that macro- and micro-nutrients maycontribute to the epidemic of NAFLD. Specifically, increased fructose consumption has been shown toincrease the risk of NAFLD [76]. Fructose is not only a major contributor in development of hepaticsteatosis but is a risk factor for promoting progression to NASH [77]. It is thought to be secondary to denovo lipogenesis and inflammatory responses promoted by increasing blood glucose levels that leadto hepatocyte apoptosis via the c-Jun-N-Terminal (JNK) pathway [78]. The consumption of beverageswith high sugar content has increased five-fold in the US since 1950—a concerning trend. There isevidence linking regular intake of servings with sugar-containing beverages for 6 months to featuresconsistent with NAFLD [79]. Omega-3-fatty acids has also been shown to be effective in reducinghepatic fat accumulation in patients with NAFLD. A meta-analysis including 10 randomized controlledtrials with 577 patients of NAFLD revealed Omega-3-fatty acids to be effective in reducing hepatic fatcontent in patients with NAFLD and NASH [80]. The Mediterranean diet has also been shown to bebeneficial in patients with NAFLD. The Mediterranean diet consists of fruits, vegetables, olive oil, andnuts, which are high in omega-3-fatty acids and antioxidants. Baratta et al., in a study including 584patients, revealed adherence to the Mediterranean diet was associated with lower insulin resistanceand reduced risk of NAFLD [81]. Therefore, experts recommend the use of the Mediterranean diet forweight loss and protection against NAFLD [82,83]. There are several other micro- and macronutrientsthat may influence the development of NAFLD, but detailed discussion of the nutrients is beyondthe scope of this review. Other comorbidities, such as hypothyroidism, hypopituitarism, polycysticovarian disease, and obstructive sleep apnea, that are also associated with NAFLD require furtherinvestigations to strengthen their associations [58].4. Diagnostic Challenges in NAFLDThe diagnosis of NAFLD involves an appropriate clinical history, radiographic and laboratoryinvestigations, and histologic information. Diagnosing NAFLD requires evidence of hepatic steatosisin the absence of significant alcohol consumption, other causes of hepatic steatosis, and coexistingliver diseases. The use of abdominal imaging can be used to diagnose NAFLD, thus limiting the needfor invasive procedures, such as liver biopsies. However, a liver biopsy is useful when differentiatingbetween simple steatosis (NAFL) and NASH. For this reason, a liver biopsy can assist with determiningthe risk of disease progression and subsequent management of NAFLD [58,84].Medicines 2019, 6, 41 9 of 194.1. Role of Liver Biopsy in the Diagnosis of NAFLDThe early diagnosis of NASH has crucial management implications, as patients can benefit fromnewly approved medications and off-label therapies to retard the progression of liver disease [57,67].Unfortunately, a liver biopsy is needed to confirm the characteristic histologic features of NASH priorto making a diagnosis. For this reason, the considerable disease burden of NASH in the US and theinvasive nature of a liver biopsy has prompted experts to recommend its selective use only in NAFLDpatients with higher likelihoods of progression to NASH. Therefore, an individualized assessmentconsidering the risks and benefits regarding a diagnostic liver biopsy is warranted. Generally, aliver biopsy is reserved for scenarios where the clinical suspicion of NAFLD is high but noninvasivemodalities are inconclusive, where there is evidence of cirrhosis or in patients who are at a high risk foradvanced fibrosis. The NAFLD activity score (NAS) is widely used for the histopathological diagnosisof NASH [58]. The NAS score considers three important histological features in a biopsy specimenwhich include steatosis, hepatocellular ballooning, and lobular inflammation. Table 4 describes theNAS score for the diagnosis of NASH. The CRN scoring system is widely used to assess the extentof fibrosis in biopsy specimens in patients with NAFLD [84]. Table 5 describes the CRN histologicalscoring system for the diagnosis of NAFLD. An important consideration is inter-observer variabilitythat can occur during the histologic evaluation of liver biopsy samples even among experiencedpathologists [84,85]. The lack of agreement between pathologists regarding hepatocellular ballooningor sampling error is a limitation and may explain the lower number of patients meeting the entrycriteria for clinical trials.Table 4. The NAFLD activity score (NAS) for the histopathologic diagnosis of nonalcoholicsteatohepatitis (NASH) [84].Histological Features Extent ScoreSteatosisExtent of involvement of parenchyma by steatosis<5% 05%–33% 133%–66% 2>66% 3BallooningNo ballooned cells 0Few ballooned cells 1Many cells with ballooning 2Lobular InflammationNo inflammatory Foci per 200 Field 0<2 foci per 200 field 12–4 foci per 200 field 2>4 foci per 200 field 3NASSum of steatosis + ballooning + lobular inflammationScore 0–2 NASH unlikelyScore 3–4 BorderlineScore 5–8 Likely NASHTable 5. CRN histological scoring system for grading of fibrosis in NAFLD [84].Stage of Fibrosis CRN Scoring System0 No fibrosisStage 1 A Mild perisinusoidalStage 1 B Moderate perisinusoidalStage 1 C Portal/periportal fibrosisStage 2 Perisinusoidal and portal/periportal fibrosisStage 3 Bridging fibrosisStage 4 CirrhosisMedicines 2019, 6, 41 10 of 194.2. Noninvasive Markers for the Detection of FibrosisThe limitations of liver biopsy, the high prevalence of NAFLD, and the lack of agreement on theclinical predictors of NASH have created a niche for next-generation noninvasive biomarkers andimaging modalities to help to differentiate NAFLD from NASH. These biomarkers can be categorizedinto indirect and direct markers of fibrosis, as illustrated in Table 6. Some examples of indirectmarkers include aminotransferases, cytokeratin-18, and multiple scoring systems which combinecertain laboratory markers, such as the aspartate aminotransferase (AST)/platelet ratio index (APRI),NAFLD Fibrosis Score (NFS), FIB-4 index, and Fibrotest. Direct markers of fibrosis comprise theextracellular matrix (ECM). such as hyaluronic acid (HA), fibronectin, elastin, and laminin, which formin the setting of persistent hepatocyte injury and have also been incorporated into certain scores. Thesemarkers are discussed in detail below.Table 6. Noninvasive serologic tests for the diagnosis of NAFLD.Serologic Test Component of the Test Clinical UtilityAminotransferases [86] ALT and AST May be elevated in NAFLD patientsCytokeratin-18 [87] Cytokeratin-18 Elevated levels in NASH patientsAST/platelet ratio index (APRI) [88] AST and platelets Predicting fibrosisNAFLD fibrosis score (NFS) [89,90]Age, BMI, blood glucose levels,aminotransferase levels, platelet count,and albuminPredicting advanced fibrosis andclinical outcomes in NAFLD patientsFIB-4 index [90,91] Age, AST, ALT and platelet count Predicting advanced fibrosis andclinical outcomes in NAFLD patientsFibroTest [92–94]Age, sex, alpha-2-macroglobulin,haptoglobin, gamma globulin,apolipoprotein A1, gamma glutamyltransferase and total bilirubin levelsPredicting extent of fibrosisActiTest [93,94]Age, sex, alpha-2-macroglobulin,haptoglobin, gamma globulin,apolipoprotein A1, gamma glutamyltransferase and total bilirubin andALT levelsPredicting necroinflammatory activityEnhanced Liver Fibrosis panel(ELF) [95,96]Matrix metalloproteinase 1 (MMP-1), HAand amino-terminal propeptide of type IIIcollagen levelPredicting extent of fibrosisFibroSpect II [97]Hyaluronic acid, tissue inhibitor ofmetalloproteinase-1 (TIMP-1), andalpha-2-macroglobulin.Predicting extent of fibrosis4.3. Indirect Markers of Fibrosis4.3.1. AminotransferasesElevations of alanine aminotransferase levels (ALT) and aspartate aminotransferases (AST) canbe found in patients with NAFLD, although normal levels do not exclude the presence of NAFLD orNASH. When elevated, these patients usually have AST to ALT ratios of less than 1, unlike alcoholicliver disease, which typically demonstrates ratios greater than 2. A retrospective study by Vermaet al. reported the prevalence of NASH in patients with elevated ALT levels (>35 U/L) to be 28.9%compared to the normal ALT group, which had a frequency close to 10.7%. Additionally, there was nodifference in the rate of advanced fibrosis between the normal and elevated ALT group. The study alsorevealed that ALT levels two times the upper limit of normal have limited utility in predicting NASH,with a sensitivity and specificity of 50% and 61%, respectively [86].4.3.2. Cytokeratin-18Multiple studies have found elevated levels of cytokeratin-18 (CK-18) fragments in patients withNASH and have shown that elevated levels of CK-18 can be a predictor of NASH in patients withMedicines 2019, 6, 41 11 of 19NAFLD [87]. Although promising, the commercial unavailability of these tests and the lack of aclear cutoff point are factors which limit its clinical use in the diagnosis of NASH. Further studies arerequired to further establish the clinical utility of CK-18 in NAFLD.4.3.3. AST/Platelet Ratio Index (APRI)APRI is a ratio of ALT levels and platelets that has been used to predict advance fibrosis primarilyin HIV and HCV patients with limited evidence in the NAFLD population. A meta-analysis including40 studies showed that the APRI ratio had a sensitivity and specificity of 77% and 72%, respectively,when predicting for significant fibrosis [88].4.3.4. NAFLD Fibrosis ScoreThe NAFLD fibrosis score (NFS) is a score used to evaluate the possibility of advanced fibrosis inpatients with NAFLD and is also used to predict outcomes in patients with NAFLD. NFS considers apatient’s age, BMI, blood glucose levels, aminotransferase levels, platelet count, and albumin. In avalidation study, a high NAFLD fibrosis score cutoff (>0.676) was associated with a positive predictivevalue of 90 percent, and a low cutoff value (<−1.455) was associated with a negative predictive valueof 93 percent [89]. A retrospective study by Angulo et al. in patients with NAFLD revealed the areaunder the ROC curve using NFS was 0.86 for predicting adverse liver-related outcomes and 0.70 forpredicting mortality or liver transplantation [90].4.3.5. FIB-4 IndexFIB-4 incorporates a patient’s age, AST, ALT, and platelet count to evaluate advanced fibrosis.FIB-4 has been shown to be better at predicting advanced fibrosis when compared to other serologictests [91]. FIB-4 is also helpful in predicting outcomes in patients with NAFLD. The previousretrospective study by Angulo et al. further evaluated the FIB-4 index and revealed the area under theROC curve was 0.81 for predicting adverse liver-related outcomes and 0.67 for predicting death orliver transplantation [90].4.3.6. FibroTest, FibroSure, and ActiTestFibroTest includes the assessment of a patient’s age, sex, alpha-2-macroglobulin, haptoglobin,gamma globulin, apolipoprotein A1, gamma glutamyl transferase, and total bilirubin levels to predictthe extent of fibrosis [92,93]. ActiTest is similar to FibroTest, but it incorporates ALT levels [93].A meta-analysis including 1570 patients revealed that these noninvasive proprietary tests were reliablealternatives to liver biopsy in patients with chronic HCV [94].4.4. Direct Markers for FibrosisThe liver is capable of hepatic regeneration when injured. When exposed to severe insults,however, hepatocytes can be replaced by components of the extracellular matrix (ECM), such ashyaluronic acid (HA), fibronectin, elastin, and laminin. These markers of ECM are attractive targets topredict fibrosis in NAFLD patients and are currently under investigation [95–97].4.4.1. Enhanced Liver Fibrosis panel (ELF)ELF is a commercially available panel that incorporates matrix turnover markers, such as matrixmetalloproteinase 1 (MMP-1), HA, and amino-terminal propeptide of type III collagen level to predictliver fibrosis [95]. ELF is marginally better than NFS in predicting fibrosis, but the combination ofthese two tests has been shown to remarkably enhance the detection of fibrosis [96].Medicines 2019, 6, 41 12 of 194.4.2. FibroSpect IIThe FibroSpect II panel consists of serum HA, tissue inhibitor of metalloproteinase-1 (TIMP-1),and alpha-2-macroglobulin. In a retrospective of study of 129 morbidly obese patients undergoinggastric bypass, Fibrospect II had a negative predictive value of 100% to predict advance fibrosis andcan be used as a useful panel to rule out significant fibrosis in NAFLD patients [97].4.5. Abdominal Imaging Modalities for Assessing Hepatic SteatosisA variety of imaging modalities can be utilized for the diagnosis of NAFLD as displayed in Table 7.These range from common radiologic techniques, such as ultrasound (US), computed tomography(CT), and magnetic resonance imaging (MRI), to methods measuring hepatic stiffness, such as magneticresonance elastography (MRE) and Transient elastography (TE) (Fibroscan).Table 7. Imaging modalities for the diagnosis of NAFLD.Imaging Modality Clinical Utility LimitationsUltrasound Abdomen [98]Widely available and convenientSensitivity and specificity fordiagnosing fatty liver disease is 85%and 94% respectivelyOperator dependentLacks sensitivity in NAFLD patientswith less than 30% steatosis on liverbiopsyCT abdomen [99] Limited clinical utility indiagnosing NAFLDRadiation hazard, introducescontrast-related risks, has lowsensitivity for hepatic fat mappingMagnetic resonance spectroscopy[99–101] Allows for quantification of hepatic fat Not available on all scannerTransient Elastography (Fibroscan)[102,103]Sensitivity of 88% with a negativepredictive value of 90% in detectingadvanced fibrosisPresence of ascites, obese patients orpresence of acute inflammationMagnetic Resonance elastography[104,105]Sensitivity of 86% and specificity of91% for diagnosing advanced fibrosisLimited availability, expertise tointerpret the results, cost of theprocedure, presence of metal implants,patient’s size and claustrophobiaShear wave elastography (SWE)[106]Sensitivity of 90% and the specificityof 88% in detecting advanced fibrosisLimited evidence available currentand needs further research on itsclinical utility4.5.1. Ultrasound and Computed Tomography of the AbdomenUS of the abdomen is the most widely available test, with a meta-analysis reporting its sensitivityand specificity for diagnosing fatty liver disease as high as 85% and 94% when compared to liverbiopsy [98]. Additionally, US is a noninvasive modality that does not pose contrast-related risks andis preferred by patients over more invasive methods. US is, however, operator-dependent and thuslacks sensitivity in NAFLD patients with less than 30% steatosis on liver biopsy. Sensitivity of US indetecting hepatic steatosis also decreases in morbidly obese patients. Computed tomography (CT)is another imaging modality but requires radiation and contrast exposure, has lower sensitivity forhepatic fat mapping, and is expensive [8].4.5.2. Magnetic Resonance Imaging and Magnetic Resonance SpectroscopyMagnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) provide thehighest precision (sensitivity and specificity) in quantifying steatosis and liver fat mapping whencompared to other imaging modalities. With promising initial data, MRI and MRS may become thegold standard for the diagnosis and management of NAFLD in the near future, although the cost ofsuch imaging is still a significant health and economic barrier [99–101].Alternatively, hepatic stiffness measurements with noninvasive methods like MRE and TE canalso be used to stratify patients into advanced and nonadvanced fibrosis groups [102,104,105,107].Medicines 2019, 6, 41 13 of 194.5.3. Transient Elastography (Fibroscan) and Magnetic Resonance Elastography (MRE)Fibroscan and MRE are the most accurate noninvasive tests to evaluate hepatic stiffness and todifferentiate advanced and nonadvanced hepatic fibrosis. Fibroscan has a sensitivity of 88%, witha negative predictive value of 90% in detecting advanced fibrosis [102]. Comparatively, MRE has asensitivity of 86% and specificity of 91% for diagnosing advanced fibrosis by using a stiffness cutoffof 3.63 Kilopascals [104]. MRE can also help to identify individuals with steatohepatitis, even beforethe onset of significant fibrosis. NAFLD with inflammation but without fibrosis demonstrates greaterhepatic stiffness than simple steatosis and a lower mean stiffness than NAFLD with fibrosis [107].MRE is also superior to Fibroscan in diagnosing cirrhosis [105]. Limitations for using MRE includelimited availability and expertise to interpret the results, cost of the procedure, inability to be usedin the presence of metal implants, and patient-limiting factors, such as size and claustrophobia [103].Although Fibroscan is more convenient to use, its clinical utility is limited in patients with ascites,excessive abdominal fat disposition or in the presence of acute inflammation [106]. For these reasons,Fibroscan is a more appropriate modality in non-obese patients, while MRE should be considered inpatients with morbid obesity for the detection of advanced fibrosis.In summary, the diagnosis of NAFLD can be made by combining appropriate noninvasiveserologic tests and imaging modalities and may help in reducing the need for liver biopsies. Studieshave shown that these noninvasive markers of liver fibrosis can differentiate between the absence offibrosis and mild fibrosis from advanced bridging fibrosis or cirrhosis. However, noninvasive tests lackthe ability to reliably detect intermediate or moderate grade fibrosis and are not useful in staging theextent of hepatic injury. For this reason, liver biopsy remains the gold standard test when diagnosingNAFLD and when evaluating advanced fibrosis and should be considered when the diagnosis remainsunclear despite noninvasive testing.5. ConclusionsNAFLD is a complex entity that overlaps significantly with insulin resistance and inflammatorystates, including the components of metabolic syndrome. Furthermore, there is emerging evidencehighlighting the importance of genetic predisposition, environmental exposures, clinical factors, anddemographical differences in NAFLD. Several studies illustrate the importance of nonpharmacologicand pharmacologic measures in reducing the incidence and progression of NAFLD. The need for earlyintervention can only be stressed further with evidence linking NALD with increased cardiovascularmortality. For these reasons, efforts should be made to effectively screen and treat for NAFLD andits associated risk factors to impede the progression of this serious disease, which currently lacks adefinite treatment.Author Contributions: U.I., B.J.P. and D.A. performed the literature search and prepared the body of themanuscript. D.K. and A.A. is a senior author who provided critical comments and updated the body of themanuscript with recent literature and reference. All the authors approved the final version of the manuscript.Funding: This research received no external funding.Conflicts of Interest: The authors declare no conflict of interest.References1. Younossi, Z.M.; Stepanova, M.; Afendy, M.; Fang, Y.; Younossi, Y.; Mir, H.; Srishord, M. Changes in theprevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008.Clin. Gastroenterol. Hepatol. 2011, 9, 524–530. [CrossRef] [PubMed]2. 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Nonalcoholic fatty liver disease
Nonalcoholic steatohepatitis
NAFLD
NASH
Liver biopsy
The Epidemiology, Risk Profiling and Diagnostic Challenges of Nonalcoholic Fatty Liver Disease
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