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Natural History of Simple Steatosis or Nonalcoholic Fatty Liver

  • Arka De
    Affiliations
    Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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  • Ajay Duseja
    Correspondence
    Address for correspondence: Dr Ajay Duseja MD, DM, FAMS, FAASLD, FACG, FSGEI, Professor, Department of Hepatology Sector 12, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
    Affiliations
    Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Published:October 23, 2019DOI:https://doi.org/10.1016/j.jceh.2019.09.005

      Abstract

      The histological spectrum of nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis and hepatocellular carcinoma. Ballooning degeneration of hepatocytes with or without fibrosis is the key feature that differentiates NASH from NAFL. Liver biopsy is the only reliable method for diagnosing NAFL and differentiating it from NASH. Although the epidemiology of NAFLD is well described, the need for invasive biopsy limits our knowledge of the community prevalence of NAFL. Recent data suggest that the biochemical composition of hepatic steatosis may have a bearing on the disease. Triglycerides, the most commonly accumulated lipid, have a cytoprotective role because of their inert nature. Several paired liver biopsy studies and longitudinal follow-up studies have shown that NAFL is not completely benign as previously envisaged. NAFL can indeed progress to NASH and severe fibrosis, with progression being influenced by presence of baseline or worsening metabolic risk factors. Overall, NAFL carries a low risk of liver-related and overall mortality although the risk of cardiovascular mortality is similar to that of NASH. Current concepts suggest the presence of a dynamic bidirectional cycling between NAFL and NASH with slow progression of fibrosis in majority of the patients. The fact that ultimately it is the onset of progressive fibrosis that dictates clinical outcomes brings into question the relevance of distinguishing NAFL from NASH.

      Keywords

      The histological spectrum of nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis and hepatocellular carcinoma (HCC). Although both NAFL and NASH are characterised by hepatic steatosis ≥5%, NASH additionally requires the presence of inflammation with hepatocyte ballooning degeneration with or without fibrosis.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      The presence of hepatic steatosis with lobular inflammation alone in the absence of ballooning degeneration is consistent with the diagnosis of NAFL. Thus, ballooning degeneration of hepatocytes is the hallmark of NASH. Steatosis in NAFLD may be macrovesicular or mixed, but the presence of microvesicular steatosis brings the diagnosis into question. Traditional concepts envisage NAFL to be benign, with NASH being the progressive form of the disease with increased liver-related and cardiovascular morbidity and mortality.
      In this review, we will discuss the natural history of simple steatosis or NAFL and try to ascertain whether it is truly benign. We will also touch on the dynamic nature of early NAFLD and revisit the need for distinguishing between NAFL and NASH in light of current evidence.

      Distinguishing NAFL from NASH

      Although emerging evidence suggests that the spectrum of NAFLD is more dynamic than that of NAFL and NASH, this distinction has been considered prognostically important, with NAFL being considered to be the more indolent form with a low risk of progression to cirrhosis. Up to a third of patients with NAFLD present with nonspecific complaints, and as such these are not helpful in differentiating NAFL from NASH. The risk of NASH is increased in advanced age (>45 years), male sex and patients with multiple metabolic syndrome risk factors including diabetes, hypertension, obesity and dyslipidemia.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      • Duseja A.
      • Singh S.P.
      • Saraswat V.A.
      • et al.
      Non-alcoholic fatty liver disease and metabolic syndrome-position paper of the Indian National Association for the study of the liver, endocrine society of India, Indian college of cardiology and Indian society of gastroenterology.
      • Wong V.W.-S.
      • Chan W.-K.
      • Chitturi S.
      • et al.
      Asia-pacific working party on non-alcoholic fatty liver disease guidelines 2017-Part 1: definition, risk factors and assessment.
      Transaminases have a poor correlation with histologic severity and do not totally differentiate between NAFL and NASH.
      • Mofrad P.
      • Contos M.J.
      • Haque M.
      • et al.
      Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values.
      Various biomarkers have been tested for differentiating NASH from NAFL. Among them, the largest body of data exists with cytokeratin 18 (CK-18). CK-18 is a marker of apoptosis, which is a hallmark of steatohepatitis. The pooled area under curve (AUROC) of CK-18 for detecting NASH is 0.82 (0.76–0.88), with a sensitivity of 66–78% and specificity of 82–87%.
      • Kwok R.
      • Tse Y.-K.
      • Wong G.L.-H.
      • et al.
      Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease - the role of transient elastography and plasma cytokeratin-18 fragments.
      ,
      • Musso G.
      • Gambino R.
      • Cassader M.
      • Pagano G.
      Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.
      Nonetheless, the lack of a commercially available test, low sensitivity and heterogeneity of proposed cut-offs and associated diagnostic accuracies preclude its use as a routine clinical investigation.
      • Castera L.
      • Friedrich-Rust M.
      • Loomba R.
      Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease.
      Liver biopsy thus remains the only method for differentiating NASH from NAFL. However, biopsies sample <1 of 50,000 of the total liver volume. Histologic features of NASH may not be evenly distributed throughout the liver parenchyma. High sampling variability was demonstrated in a study that looked at the agreement between paired biopsies in patients with NAFLD. The discordance rate for the presence of hepatocyte ballooning was 18%, with the negative predictive value of a single biopsy in ruling out NASH being only 0.7.
      • Ratziu V.
      • Charlotte F.
      • Heurtier A.
      • et al.
      Sampling variability of liver biopsy in nonalcoholic fatty liver disease.
      To minimise sampling error, liver biopsy should be performed using at least a 16-gauge needle with an ideal core length of 15 mm.
      • Rockey D.C.
      • Caldwell S.H.
      • Goodman Z.D.
      • Nelson R.C.
      • Smith A.D.
      Liver biopsy.
      Moreover, biopsy interpretation is affected by observer bias and is influenced by the experience of the histopathologist. Various histologic scoring systems have been suggested for standardising biopsy interpretation. Matteoni et al
      • Matteoni C.A.
      • Younossi Z.M.
      • Gramlich T.
      • Boparai N.
      • Liu Y.C.
      • McCullough A.J.
      Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
      proposed subdividing NAFLD into 4 histologic subtypes (type 1: fatty liver alone, type 2: steatosis and lobular inflammation, type 3: steatosis and hepatocyte ballooning and type 4: steatosis, ballooning degeneration and either Mallory hyaline or fibrosis). Type 1 and 2 lesions are consistent with the current definitions of NAFL. However, this system did not incorporate a scoring system for grading or staging the severity of lesions.
      • Matteoni C.A.
      • Younossi Z.M.
      • Gramlich T.
      • Boparai N.
      • Liu Y.C.
      • McCullough A.J.
      Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
      Brunt et al
      • Brunt E.M.
      • Janney C.G.
      • Bisceglie A.M.
      • Neuschwander-Tetri B.A.
      • Bacon B.R.
      Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.
      proposed a qualitative 3-tier grading system (mild, moderate and severe) by incorporating steatosis, ballooning and inflammation and a 4-tier staging system based on the location and severity of fibrosis. Although this system has been used in many studies, it should be noted that the Brunt system is specific for lesions of NASH and does not incorporate the whole spectrum of NAFLD including NAFL.
      • Brunt E.M.
      • Janney C.G.
      • Bisceglie A.M.
      • Neuschwander-Tetri B.A.
      • Bacon B.R.
      Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.
      Currently, two semiquantitative, validated scoring systems are widely used and include the sponsored NASH Clinical Research Network (CRN) system and the steatosis-activity-fibrosis (SAF) score (Table 1, Table 2). The NASH CRN system includes a NAFLD activity score (NAS) comprising an amalgamation of ballooning, lobular inflammation and steatosis scores ranging from 0 to 8 points and a separate fibrosis score ranging from 0 to 4 (Table 1). NAS cut-offs have been validated in trials, with scores <3 indicating ‘no NASH’, ≥3 and < 5 indicating ‘borderline NASH’ and ≥5 indicating ‘NASH’.
      • Kleiner D.E.
      • Brunt E.M.
      • Van Natta M.
      • et al.
      Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
      ,
      • Hjelkrem M.
      • Stauch C.
      • Shaw J.
      • Harrison S.A.
      Validation of the non-alcoholic fatty liver disease activity score.
      Although the NASH CRN system is a valuable research tool, two points need to be emphasised. First, it should not be used to diagnose or differentiate NAFLD from NASH in the individual patient. Indeed, the authors of the original study themselves acknowledge that the NAS is ‘not intended to replace the pathologist's diagnostic determination of steatohepatitis’.
      • Kleiner D.E.
      • Brunt E.M.
      • Van Natta M.
      • et al.
      Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
      Second, the application of the NAS as a prognostic tool in day-to-day practice is contentious.
      • Younossi Z.M.
      • Stepanova M.
      • Rafiq N.
      • et al.
      Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality.
      ,
      • Ekstedt M.
      • Franzén L.E.
      • Mathiesen U.L.
      • Kechagias S.
      Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression.
      The SAF score was more recently developed as a semiquantitative, reliable and reproducible score to classify NAFLD in clinical practice. It evaluates steatosis, necroinflammatory activity and fibrosis separately and subsequently uses a simple algorithm to classify patients as normal, NAFL or NASH (Figure 1).
      • Bedossa P.
      • Poitou C.
      • Veyrie N.
      • et al.
      Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients.
      The SAF score circumvents the criticism that the NAS is highly weighted for steatosis. By separating steatosis and activity scores, the SAF score is better suited for differentiating NAFL from NASH.
      Table 1NAFLD Activity Score (NAS) as per the NASH CRN System.
      Histologic featureScoreDefinition
      Steatosis0<5%
      15–33%
      234–66%
      3>66%
      +
      Hepatocyte ballooning0None
      1Few
      2Many
      +
      Lobular inflammation0None
      11–2 foci per 20 X field
      22–4 foci per 20 X field
      3>4 foci per 20 X field
      NAFLD activity score (NAS); range 0–8
      Fibrosis stage0No fibrosis
      1aZone 3 mild perisinusoidal fibrosis
      1bZone 3 moderate perisinusoidal fibrosis
      1cPortal or portal fibrosis only
      2Zone 3 + portal/periportal fibrosis
      3Bridging fibrosis
      4Cirrhosis
      NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic fatty liver disease; CRN: Clinical Research Network.
      Table 2Steatosis-Activity-Fibrosis (SAF) Score for NAFLD.
      Histologic FeatureScoreDefinition
      Steatosis0<5%
      15–33%
      234–66%
      3>66%
      Steatosis score (S 0–3)
      Hepatocyte ballooning0None
      1Clusters of round hepatocytes with pale cytoplasm
      2Same as previously mentioned with enlarged hepatocytes (>2 times than normal)
      +
      Lobular inflammation0None
      1<2 foci per 20 X field
      2>2 foci per 20 X field
      Activity score (A 0–4)
      Fibrosis0No fibrosis
      1aZone 3 mild perisinusoidal fibrosis
      1bZone 3 moderate perisinusoidal fibrosis
      1cPortal or portal fibrosis only
      2Zone 3 + portal/periportal fibrosis
      3Bridging fibrosis
      4Cirrhosis
      Fibrosis score (F 0–4)
      NAFLD: nonalcoholic fatty liver disease.
      Figure 1
      Figure 1SAF score–based algorithm for diagnosis of NAFL and NASH. NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic fatty liver disease; SAF: steatosis-activity-fibrosis.

      Composition of the steatotic liver: more than what meets the eye

      Exciting new evidence is emerging about the varying hepatotoxic potential of different intrahepatocytic lipids. The predominant lipid that accumulates in hepatic steatosis is triglycerides. So far, much of the clinical attention has been focused on triglycerides as they are abundant and are easy to be quantified using imaging or histological techniques. However, triglycerides per se are not hepatotoxic. As such, their role is protective, and they provide a buffer against toxic fat. They allow lipids to be stored in an inert form as opposed to metabolically active, toxic forms. This has been demonstrated in several animal models.
      • Raabe M.
      • Véniant M.M.
      • Sullivan M.A.
      • et al.
      Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.
      • Yu X.X.
      • Murray S.F.
      • Pandey S.K.
      • et al.
      Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice.
      • Yamaguchi K.
      • Yang L.
      • McCall S.
      • et al.
      Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis.
      There is no difference in the triglyceride content between NAFL and NASH.
      • Puri P.
      • Baillie R.A.
      • Wiest M.M.
      • et al.
      A lipidomic analysis of nonalcoholic fatty liver disease.
      The candidate toxic lipids include fatty acids, lipophosphatidylcholine, ceramides and cholesterol.
      • Puri P.
      • Baillie R.A.
      • Wiest M.M.
      • et al.
      A lipidomic analysis of nonalcoholic fatty liver disease.
      ,
      • Anjani K.
      • Lhomme M.
      • Sokolovska N.
      • et al.
      Circulating phospholipid profiling identifies portal contribution to NASH signature in obesity.
      In the future, management strategies may switch from focussing on decreasing hepatic steatosis to increasing inert depots while reducing true lipotoxic exposure. The exact reasons for some patients to have NAFL and for others to progress on to NASH are not clear but are dependent on the prevalence of metabolic risk factors in these patients. Interindividual and interethnic differences in the severity and progression of liver disease among patients with NAFLD also suggest the involvement of genetic factors in their pathogenesis. Several studies have shown association of NAFLD with I148M patatin-like phospholipase domain containing 3 gene (PNPLA3) and transmembrane 6 superfamily 2 gene variants.
      • Romeo S.
      • Kozlitina J.
      • Xing C.
      • et al.
      Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.
      ,
      • Kozlitina J.
      • Smagris E.
      • Stender S.
      • et al.
      Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.
      In addition to the higher prevalence of hepatic steatosis, the I148M PNPLA3 variant is also associated with severity of liver disease including the risk of NASH, fibrosis and HCC.
      • Sookoian S.
      • PirolaCJ
      Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.

      Prevalence of NAFL

      The global prevalence of NAFLD is around 25%.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      The prevalence of NAFLD in India in various studies ranges from 9% to 53%.
      • Duseja A.
      • Singh S.P.
      • Saraswat V.A.
      • et al.
      Non-alcoholic fatty liver disease and metabolic syndrome-position paper of the Indian National Association for the study of the liver, endocrine society of India, Indian college of cardiology and Indian society of gastroenterology.
      ,
      • Duseja A.
      • Chalasani N.
      Epidemiology and risk factors of nonalcoholic fatty liver disease (NAFLD).
      ,
      • Duseja A.
      • Najmy S.
      • Sachdev S.
      • et al.
      High prevalence of non-alcoholic fatty liver disease among healthy male blood donors of urban India.
      However, there are limited data on the prevalence of NAFL as biopsy is required for differentiating NAFL from NASH. An analysis of the National Health and Nutrition Examination Survey III database reported the prevalence of NAFLD in the United States as 18.8% and NASH as 2.6%. Thus, we can infer that the prevalence of NAFL was 16.2%. However, it should be noted that in this study, NASH was defined by the presence of elevated liver enzymes in the presence of diabetes or insulin resistance.
      • Younossi Z.M.
      • Stepanova M.
      • Negro F.
      • et al.
      Nonalcoholic fatty liver disease in lean individuals in the United States.
      A study from the Brooke Army Medical Centre showed a prevalence of 66.4% for NAFL on biopsy of patients having ultrasonographic evidence of fatty liver.
      • Williams C.D.
      • Stengel J.
      • Asike M.I.
      • et al.
      Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
      Of 38 patients with biopsy-proven NAFLD in an Indian study, NAFL (type 1 and type 2 NAFLD according to Matteoni et al) was present in 47% patients.
      • Matteoni C.A.
      • Younossi Z.M.
      • Gramlich T.
      • Boparai N.
      • Liu Y.C.
      • McCullough A.J.
      Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
      ,
      • Duseja A.
      • Das A.
      • Das R.
      • et al.
      The clinicopathological profile of Indian patients with nonalcoholic fatty liver disease (NAFLD) is different from that in the west.
      A similar prevalence of 45% for NAFL (type 1 and type 2 NAFLD according to Matteoni et al) was demonstrated among 51 patients with biopsy-proven NAFLD and transaminitis in another hospital-based study from North India.
      • Madan K.
      • Batra Y.
      • Gupta S.D.
      • et al.
      Non-alcoholic fatty liver disease may not be a severe disease at presentation among Asian Indians.
      Among 573 potential liver donors with preoperative biopsies at an Indian centre, NAFL was detected in 49.2% patients. The presence of ≥2 metabolic risk factors was a significant predictor of NAFL.
      • Choudhary N.S.
      • Saraf N.
      • Saigal S.
      • et al.
      Prediction of nonalcoholic fatty liver in prospective liver donors.

      Natural history of NAFL: evolving concepts and supporting evidence

      Knowledge about the natural history of simple steatosis or NAFL is still evolving. It was commonly believed that simple steatosis is a benign, nonprogressive condition that does not increase overall or liver-related mortality, whereas it was believed NASH is progressive with marked increase in liver-related mortality owing to cirrhosis or HCC. However, emerging data are challenging the long-lasting beliefs that NAFL is completely benign with no clinical sequelae and that NASH alone is prognostically and clinically relevant.
      • Anstee Q.M.
      • Day C.P.
      Epidemiology, natural history and evaluation of nonalcoholic fatty liver disease.
      These data come from two types of studies: serial liver biopsy studies and longitudinal follow-up studies. The former provides important information about histologic disease progression from which we can deduce the evolution of NAFL and NASH and the rate of fibrosis progression. Longitudinal follow-up of defined patient cohorts reports on the clinical course of the disease that helps study the risk of clinically relevant outcomes and prognosis.

      Histologic disease progression in NAFL

      In a prospective hospital-based cohort of 52 patients with biopsy-proven NAFLD, liver biopsies were repeated after 3 years. Among 13 patients with simple steatosis at baseline, repeat biopsies revealed normal biopsies in 2 (15%), simple steatosis in 3 (23%) and progression to borderline NASH and NASH in 5 (39%) and 3 (23%), respectively. On multivariate analysis, reduction in the body mass index and waist circumference were independently associated with nonprogressive disease activity (NASs) and fibrosis. This study provided an early insight that simple steatosis can progress to NASH with worsening fibrosis and that weight reduction may be predictive of nonprogression.
      • Wong V.W.-S.
      • Wong G.L.-H.
      • Choi P.C.-L.
      • et al.
      Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years.
      The Liver Injury in Diabetes and Obesity study group systematically reviewed 70 patients with untreated NAFLD, with serial liver biopsies performed more than 1 year apart. Twenty-five patients had NAFL at baseline. Among them, 16 developed NASH, 8 had severe ballooning and 6 developed bridging fibrosis on repeat biopsies at a mean follow-up of 3.7 ± 2.1 years. Patients with unambiguous disease progression were older and had worse baseline or worsening metabolic parameters (weight and diabetes) on follow-up. The study also revealed that presence of even mild lobular inflammation or any degree of fibrosis significantly increased the risk of disease progression.
      • Pais R.
      • Charlotte F.
      • Fedchuk L.
      • et al.
      A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver.
      In a study evaluating the usefulness of the NAS in predicting fibrosis progression, 64 patients with NAFLD, with repeat biopsies at a mean interval of 13.8 ± 1.2 years, were analysed. Of 45% patients with ‘no NASH’ (NAS < 4) at baseline, fibrosis progression was seen in 18%. Intriguingly, on multivariate analysis, it was found that the NAS was not predictive of fibrosis progression.
      • Ekstedt M.
      • Franzén L.E.
      • Mathiesen U.L.
      • Kechagias S.
      Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression.
      A systematic review and meta-analysis of paired biopsies from 11 cohort studies comprising 411 patients with histologically confirmed NAFLD (150 with NAFL and 261 with NASH) with more than 2145.5 person-years of follow-up provided interesting insights into the dynamic nature of the natural history of NAFLD. Overall, fibrosis progressed in 33.6% of patients, whereas it remained stable in 43.1% and improved in 22.3% of patients. The mean fibrosis progression rate in patients with NAFL was 0.07 stages per annum compared with 0.14 stages per annum in patients with NASH. This corresponds to fibrosis progression by 1 stage in approximately 14 years in NAFL and 7 years in NASH. Intriguingly, irrespective of the presence of NAFL or NASH on baseline biopsy, 20% patients, with no fibrosis at baseline, progressed relatively rapidly to advanced stage 3/4 fibrosis (rapid progressors), whereas 80% patients were slow progressors, with little or no progression in fibrosis.
      • Singh S.
      • Allen A.M.
      • Wang Z.
      • Prokop L.J.
      • Murad M.H.
      • Loomba R.
      Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.
      These findings were further corroborated in another cohort of 108 histologically characterised patients with NAFLD who underwent repeat liver biopsy at a median interval of 6.6 (1.3–22.6) years. Fibrosis progression was observed in 42% patients, whereas it remained stable in 40% and regressed in 18%. No significant difference in the proportion of fibrosis progressors was seen between patients with NAFL and NASH on baseline biopsy (37% vs 43%, respectively). The development of diabetes was a clinical clue of aggressive disease with 80% of patients with NAFL and progression of fibrosis having developed diabetes by the time of second biopsy compared with 25% of nonprogressors.
      • McPherson S.
      • Hardy T.
      • Henderson E.
      • Burt A.D.
      • Day C.P.
      • Anstee Q.M.
      Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management.

      Clinical outcomes of NAFL

      A cohort of 129 patients with biopsy-proven NAFLD was followed up for 13.7 ± 1.3 years, and their clinical outcomes were compared with a matched reference population. Survival of patients with NASH was significantly less than that of the reference population. But simple steatosis was not associated with increased mortality. None of the 58 patients with simple steatosis developed liver-related complications on follow-up. Development of type 2 diabetes mellitus was significantly more common in patients with NASH (71%) than in those with simple steatosis (46%). Manifested cardiovascular disease on follow-up was also significantly more common in patients with NASH (29%) than in those without it (9%).
      • Ekstedt M.
      • Franzén L.E.
      • Mathiesen U.L.
      • et al.
      Long-term follow-up of patients with NAFLD and elevated liver enzymes.
      In a Swedish cohort of 118 patients with biopsy-proven NAFLD (67 with NAFL and 51 with NASH as per NASH CRN criteria), NASH was associated with a significantly increased mortality risk compared with the Swedish general population (risk ratio [RR] = 1.86, p = 0.007), while a trend towards increased risk was seen in those with NAFL (RR = 1.55, p = 0.06) over a follow-up period of 28 years. However, no significant difference in liver-related or overall mortality was seen between NAFL and NASH. Importantly, nonsurvivors were more likely to have ≥ F3 fibrosis.
      • Söderberg C.
      • Stål P.
      • Askling J.
      • et al.
      Decreased survival of subjects with elevated liver function tests during a 28-year follow-up.
      In an American cohort of 173 patients with NAFLD (41.6% NASH and 58.4% non-NASH NAFLD), no difference was seen between the subgroups with respect to age at the time of biopsy, transaminase levels, diabetes and the body mass index. During follow-up (maximum 28.5 years), liver-related mortality emerged as the third most common cause of death (preceded by cardiac causes and malignancy) in the whole cohort. Overall mortality was not different between the NAFLD subtypes. However, liver-related mortality was higher in patients with NASH than in those with non-NASH NAFLD (hazard ratio [HR] = 13.9, p = 0.004). In this cohort of patients with NAFLD too, presence of diabetes mellitus indicated a poorer prognosis, with increased risk of both overall and liver-related mortality (HR = 2.7 and 6.7, respectively).
      • Rafiq N.
      • Bai C.
      • Fang Y.
      • et al.
      Long-Term follow-up of patients with nonalcoholic fatty liver.
      A meta-analysis of 40 articles on the natural history of NAFLD confirmed the increased risk of diabetes and mortality in NAFLD. Compared with NAFL, NASH was associated with a higher overall and liver-related mortality (odds ratio [OR]: 1.8 and 5.7, respectively). However, cardiovascular mortality in NASH was not significantly different from NAFL (OR: 0.91).
      • Musso G.
      • Gambino R.
      • Cassader M.
      • Pagano G.
      Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.
      Although occurrence of HCC is more common in patients with fibrotic NASH and NASH-related cirrhosis, the recent literature suggests the development of HCC even in patients with NAFL, without any evidence of fibrosis.
      • Kawada N.
      • Imanaka K.
      • Kawaguchi T.
      • et al.
      Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis.
      ,
      • Paradis V.
      • Zalinski S.
      • Chelbi E.
      • et al.
      Hepatocellular carcinoma in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.
      In reference to extrahepatic manifestations, as mentioned earlier, cardiovascular disease and development of type 2 diabetes mellitus on follow-up is more common in patients with NASH than in those without it.
      • Ekstedt M.
      • Franzén L.E.
      • Mathiesen U.L.
      • et al.
      Long-term follow-up of patients with NAFLD and elevated liver enzymes.
      In a cohort of liver donors with preoperative biopsies, no difference in estimated glomerular filtration rates or proteinuria was noted between patients with biopsy-proven NAFL (n = 187) and patients with normal histology (n = 188). No difference in diabetes and hypertension was observed between the two groups.
      • Choudhary N.S.
      • Saraf N.
      • Kumar N.
      • et al.
      Nonalcoholic fatty liver is not associated with incident chronic kidney disease.
      On the other hand, we observed that around one-third of patients with NAFLD have impaired renal functions and the prevalence of impaired renal function in patients with NAFLD was dependent on the severity of liver disease and presence of diabetes mellitus.
      • Nampoothiri R.V.
      • Duseja A.
      • Rathi M.
      • et al.
      Renal dysfunction in patients with nonalcoholic fatty liver disease is related to the presence of diabetes mellitus and severity of liver disease.
      Of the other extrahepatic manifestations, significant hepatic fibrosis in patients with NAFLD has been shown to be related to obstructive sleep apnoea, independent of obesity and metabolic syndrome.
      • Agrawal S.
      • Duseja A.
      • Aggarwal A.
      • et al.
      Obstructive sleep apnea is an important predictor of hepatic fibrosis in patients with nonalcoholic fatty liver disease in a tertiary care center.

      Dynamic model of NAFLD

      It is clear that although in some patients, NAFL can progress to NASH and advanced fibrosis, NASH can also regress to NAFL over time. Thus, the presence of NAFL or NASH on baseline histologic examination provides little overall prognostic information, although patients with NAFL may be at the lowest risk of progression. Current concepts suggest a dynamic cycling between NAFL and NASH in the early stage of NAFLD.
      • Anstee Q.M.
      • Day C.P.
      Epidemiology, natural history and evaluation of nonalcoholic fatty liver disease.
      Among patients developing some hepatic fibrosis, 80% exhibit slow progression that is not likely to progress beyond mild (F0–F2) fibrosis. However, rapid progression of fibrosis to F3/F4 in few years is seen in approximately 20% patients (Figure 2). Relatively advanced stages of fibrosis seen in NASH (compared with NAFL) may be explained by a longer duration of disease and the observation that NASH is usually preceded by steatosis. Lending credence to the explanation, in a recent study, patients with NASH were found to be older than those with NAFL by 9 years.
      • McPherson S.
      • Hardy T.
      • Henderson E.
      • Burt A.D.
      • Day C.P.
      • Anstee Q.M.
      Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management.
      The focus should now centre on the correct and timely identification of the relatively small cohort of rapid progressors. Diabetes mellitus appears to be a major risk factor for rapid progression.
      • Singh S.
      • Allen A.M.
      • Wang Z.
      • Prokop L.J.
      • Murad M.H.
      • Loomba R.
      Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.
      Figure 2
      Figure 2Dynamic model of NAFLD (adapted from Anstee and Day [33]. Epidemiology, natural history and evaluation of nonalcoholic fatty liver disease. In: Zakim and Boyer's hepatology: a textbook of liver disease. 7th ed. 2017. p. 394). NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic fatty liver disease.

      Relevance of differentiating NAFL from NASH in light of current evidence

      A wealth of evidence now suggests that the degree of fibrosis is the only critical predictor of outcomes in NAFLD.
      • Angulo P.
      • Kleiner D.E.
      • Dam-Larsen S.
      • et al.
      Liver fibrosis, but No other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.
      • Ekstedt M.
      • Hagström H.
      • Nasr P.
      • et al.
      Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
      • Ekstedt M.
      • Nasr P.
      • Kechagias S.
      Natural history of NAFLD/NASH.
      As previously discussed, the histologic differentiation between NAFL and NASH does not predict fibrosis progression and carries little prognostic information.
      • Ekstedt M.
      • Franzén L.E.
      • Mathiesen U.L.
      • Kechagias S.
      Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression.
      ,
      • Singh S.
      • Allen A.M.
      • Wang Z.
      • Prokop L.J.
      • Murad M.H.
      • Loomba R.
      Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.
      ,
      • McPherson S.
      • Hardy T.
      • Henderson E.
      • Burt A.D.
      • Day C.P.
      • Anstee Q.M.
      Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management.
      ,
      • Angulo P.
      • Kleiner D.E.
      • Dam-Larsen S.
      • et al.
      Liver fibrosis, but No other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.
      ,
      • Ekstedt M.
      • Hagström H.
      • Nasr P.
      • et al.
      Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
      This is due to the dynamicity seen in early NAFLD (without significant fibrosis) with cycling between NAFL and NASH such that a single snapshot at the time of biopsy has limited clinical relevance. However, progressive fibrosis portends a poor prognosis with adverse cardiovascular and liver-related outcomes. Expanding on this concept, a recent Nature review has called for a revision of the definition of NAFLD to include only patients with advanced fibrosis by drawing parallels with patients with coronary artery disease. They suggest that patients with NAFL or NASH with early fibrosis (F0–F2) need not be considered as having liver disease requiring diagnosis or intervention because of the low risk of liver-related mortality. Metabolic risk factors such as diabetes should be treated in these patients to improve cardiovascular outcomes, with possible benefits on liver disease. On the contrary, liver-related mortality rates in those with F3 or F4 fibrosis approximate cardiovascular mortality risks in patients with cardiovascular risk factors who qualify for primary prevention of coronary artery disease and statin therapy. It is this subgroup of patients who thus merit a specific diagnosis and need to be identified for liver-specific intervention.
      • Rowe I.A.
      • Parker R.
      The diagnosis of nonalcoholic fatty liver disease should carry important prognostic information.
      Another implication of the dynamic nature of early NAFLD is that studies should consider reduction in fibrosis as an endpoint instead of reduction in the NAS or resolution of NASH. Resolution of NASH is diagnosed by the absence of ballooning degeneration, which is affected by interobserver and sampling variability. Steatofibrosis is less susceptible to interobserver variability although some sampling bias does exist. Moreover, it is a predictor of both overall and liver-related mortality. Thus, it may be better suited for use in clinical trials than resolution of NASH or decrease in the NAS.
      • Younossi Z.M.
      • Stepanova M.
      • Rafiq N.
      • et al.
      Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty liver disease.
      As mentioned earlier, there is accumulating evidence that HCC can occur in NAFLD even in the absence of significant fibrosis, particularly in older men.
      • Kawada N.
      • Imanaka K.
      • Kawaguchi T.
      • et al.
      Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis.
      ,
      • Paradis V.
      • Zalinski S.
      • Chelbi E.
      • et al.
      Hepatocellular carcinoma in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.
      Hence, using steatofibrosis as the sole histologic determinant of meaningful clinical outcomes warrants caution.
      NAFLD may be considered as a clinicopathological spectrum with differential subtypes with differential potential for progression. NAFL or simple steatosis should not be perceived as completely innocuous or simple. Longitudinal histological data suggest that NAFL can progress to NASH and severe fibrosis, with progression being influenced by worsening metabolic risk factors and presence of fibrosis at baseline. Clinical progression to end-stage liver disease, liver-related mortality and overall mortality is worse in NASH than in NAFL. However, risk of cardiovascular mortality remains the same. Although much remains unanswered about the natural history of NAFL, the presence of diabetes mellitus has consistently been found to be a harbinger of poorer outcomes. Current concepts suggest the presence of a dynamic bidirectional cycling between NAFL and NASH, with slow progression of fibrosis in majority of the patients. Ultimately, it is not the distinction between NAFL and NASH but the onset of progressive fibrosis that is the key determinant of NAFLD outcomes.

      Conflicts of interest

      The authors have none to declare.

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