Toward More Accurate Nomenclature for Fatty Liver Diseases

The spectrum of fatty liver disease, encompassing alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD), is today the most common cause of chronic liver injury. However, while in common parlance the terms are used to refer to distinct disorders, both diseases have significant overlap in pathogenesis and their genetic architecture, and frequently coexist.1Anstee Q.M. Seth D. Day C.P. Genetic factors that affect risk of alcoholic and nonalcoholic fatty liver disease.Gastroenterology. 2016; 150: 1728Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 2Eslam M. George J. Genetic and epigenetic mechanisms of NASH.Hepatol Int. 2016; 10: 394-406Crossref PubMed Scopus (27) Google Scholar, 3Eslam M. Valenti L. Romeo S. Genetics and epigenetics of NAFLD and NASH: Clinical impact.J Hepatol. 2018; 68: 268-279Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar According to the World Health Organization 2018 global status report, >3 million deaths every year, representing around 5% of global deaths, are attributable to alcohol consumption.4World Health OrganizationGlobal status report on alcohol and health 2018. World Health Organization, Geneva2018Google Scholar Likewise, the prevalence of NAFLD is increasing and currently affects a quarter of the global populace, with both hepatic and extrahepatic consequences.5Younossi Z. Anstee Q.M. Marietti M. et al.Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.Nat Rev Gastroenterol Hepatol. 2018; 15: 11-20Crossref PubMed Scopus (1391) Google Scholar In the UK, liver disease is predicted to overtake ischemic heart disease as a leading cause of years of working life lost, surpassing lung and breast cancers.6Williams R. Alexander G. Armstrong I. Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet Standing Commission on Liver Disease in the UK (vol 391, pg 1097, 2018).Lancet. 2018; 391 (1022-1022)Abstract Full Text Full Text PDF Scopus (82) Google Scholar Since the first description of NAFLD by Ludwig et al7Ludwig J. Viggiano T.R. McGill D.B. et al.Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.Mayo Clin Proc. 1980; 55: 434-438PubMed Google Scholar in 1980, the criteria for the diagnosis of NAFLD and the appropriateness and accuracy of the nomenclature has not been revisited. Heterogeneous prior definitions are reflected in limitations in our ability to accurately define the natural history of NAFLD, to compare or pool results from clinical trials, or to anchor non–biopsy-based diagnostic development. Stemming from this need, the Liver Forum (2018) made recommendations on NAFLD case definitions based on a description of phenotype (fatty liver vs steatohepatitis), activity, disease stage, and disease etiology.8Siddiqui M.S. Harrison S.A. Abdelmalek M.F. et al.Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science.Hepatology. 2018; 67: 2001-2012Crossref PubMed Scopus (62) Google Scholar Currently, the definition of NAFLD and the distinction from AFLD is based solely on the amount of alcohol consumed, whereas the forum definition assumes that excessive alcohol consumption has been excluded. As an extension of this work, we discuss the core etiologic definition for NAFLD that is, to a significant degree, based on alcohol consumption (without any mention of metabolic dysfunction), and suggest the need to empirically reevaluate the literature to arrive at a more contemporary consensus. For NAFLD, it is assumed that the amount of alcohol consumed is below the threshold where alcohol would have a significant impact on clinical phenotype, disease progression, and outcomes.9Chalasani 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.Hepatology. 2018; 67: 328-357Crossref PubMed Scopus (1989) Google Scholar Although, there is no agreement on the threshold of alcohol use that rules out NAFLD, a level of 30 g/d for men and 20 g/d for women is commonly used.9Chalasani 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.Hepatology. 2018; 67: 328-357Crossref PubMed Scopus (1989) Google Scholar, 10European Association for the Study of the Liver (EASL)European Association for the Study of Diabetes (EASD)European Association for the Study of Obesity (EASO)EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.J Hepatol. 2016; 64: 1388-1402Abstract Full Text Full Text PDF PubMed Scopus (1687) Google Scholar Light (1.0-9.9 g/d) or moderate (10.0–29.9 g/d; 10.0–19.9 g/d for women) alcohol consumption in patients with NAFLD is not uncommon. For example, it has been reported that nearly two-thirds of adult patients with NAFLD in the United States drink alcohol, most of whom drink in moderation (∼ 4 drinks/week).11Saad L. Majority in US drink alcohol, averaging four drinks a week.Gallup Well-Being. 2012, August 17; Google Scholar From a liver disease perspective, there has been a longstanding controversy on the impact of moderate alcohol consumption on the prognosis of NAFLD, with some studies suggesting protective effects,12Dunn W. Sanyal A.J. Brunt E.M. et al.Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD).J Hepatol. 2012; 57: 384-391Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 13Kwon H.K. Greenson J.K. Conjeevaram H.S. Effect of lifetime alcohol consumption on the histological severity of non-alcoholic fatty liver disease.Liver Int. 2014; 34: 129-135Crossref PubMed Scopus (61) Google Scholar whereas others report increased risks.14Ekstedt M. Franzén L.E. Holmqvist M. et al.Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease.Scand J Gastroenterol. 2009; 44: 366-374Crossref PubMed Scopus (129) Google Scholar, 15Ascha M.S. Hanouneh I.A. Lopez R. et al.The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.Hepatology. 2010; 51: 1972-1978Crossref PubMed Scopus (804) Google Scholar More recently, there is convincing evidence that there is no safe limit for alcohol consumption—a limit that is not associated with either liver or even cardiovascular complications. The most comprehensive assessment of the worldwide burden of alcohol use is the systematic analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for 195 countries and territories, published in 2018. That study of 28 million individuals and 649,000 cases with outcomes, suggested that there is no safe limit for alcohol use.16Meltzer-Brody S. Colquhoun H. Riesenberg R. GBD 2016 Alcohol CollaboratorsAlcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016 (vol 392, pg 1015, 2018).Lancet. 2018; 392 (1116-1116)PubMed Google Scholar Another study of 6732 Finnish individuals without baseline liver disease with an average follow-up of 11 years, demonstrated that alcohol use was a significant risk factor for progression of liver disease (even within the currently used limits defining NAFLD).17Aberg F. Helenius-Hietala J. Puukka P. et al.Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population.Hepatology. 2018; 67: 2141-2149Crossref PubMed Scopus (89) Google Scholar Similarly, in a recent study of 58,927 Korean subjects with NAFLD and low baseline fibrosis scores who were followed for a median of 4.9 years, light (1.0–9.9 g/d) or moderate (10.0–29.9 g/d (10.0–19.9 g/d for women) alcohol consumption compared with none (0 g/d) was significantly and independently associated with worsening of fibrosis, assessed by noninvasive markers (AST to Platelet Ratio Index and Fibrosis-4). This was more profound with moderate alcohol consumption.18Chang Y. Cho Y.K. Kim Y. et al.Nonheavy drinking and worsening of noninvasive fibrosis markers in nonalcoholic fatty liver disease: a cohort study.Hepatology. 2019; 69: 64-75Crossref PubMed Scopus (51) Google Scholar Similarly, in the Finnish study alluded to earlier, among persons with alcohol use within the limits used to define NAFLD, alcohol use was a significant risk factor for incident liver disease. The authors suggest that that a safe limit of alcohol use with regard to liver risk may not exist.17Aberg F. Helenius-Hietala J. Puukka P. et al.Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population.Hepatology. 2018; 67: 2141-2149Crossref PubMed Scopus (89) Google Scholar In another report on 4264 individuals from the National Health and Nutrition and Examination Survey III for adults with hepatic steatosis diagnosed by ultrasound examination and followed for ≤20 years, excessive alcohol consumption, defined as >3.0 and 1.5 drinks per day, for men and women, respectively, was associated with increased mortality; this effect was more profound in subjects with the metabolic syndrome.19Younossi Z.M. Stepanova M. Ong J. et al.Effects of alcohol consumption and metabolic syndrome on mortality in patients with non-alcoholic and alcohol-related fatty liver disease.Clin Gastroenterol Hepatol. 2019; 17: 162-1633Abstract Full Text Full Text PDF Scopus (48) Google Scholar The negative impact of alcohol intake also extends to nonalcoholic steatohepatitis resolution. In a recent longitudinal study of patients with NAFLD with paired biopsies, low to modest alcohol consumption was associated with less improvement in steatosis and nonalcoholic steatohepatitis, compared with no alcohol intake.20Ajmera V. Belt P. Wilson L.A. et al.Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis.Clin Gastroenterol Hepatol. 2018; 16: 1511-1520Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Further evidence comes from a Mendelian randomization study that used an alcohol-use related genetic variant as a proxy for alcohol use, thereby minimizing measurement bias and confounding. This report suggested that the genotype associated with light to moderate alcohol use was associated with increased steatosis, lobular inflammation, and NAS score.21Sookoian S. Flichman D. Castano G.O. et al.Mendelian randomisation suggests no beneficial effect of moderate alcohol consumption on the severity of nonalcoholic fatty liver disease.Aliment Pharmacol Ther. 2016; 44: 1224-1234Crossref PubMed Scopus (24) Google Scholar The impact of alcohol use on liver disease seems to have a dose–response curve, with a direct relationship between the quantity of alcohol consumed and liver disease progression, rather than a single J-shaped association.22Lackner C. Tiniakos D. Fibrosis and alcohol-related liver disease.J Hepatol. 2019; 70: 294-304Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 23Rehm J. Taylor B. Mohapatra S. et al.Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis.Drug Alcohol Rev. 2010; 29: 437-445Crossref PubMed Scopus (360) Google Scholar The negative impact is aggravated in the context of the metabolic syndrome.17Aberg F. Helenius-Hietala J. Puukka P. et al.Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population.Hepatology. 2018; 67: 2141-2149Crossref PubMed Scopus (89) Google Scholar, 19Younossi Z.M. Stepanova M. Ong J. et al.Effects of alcohol consumption and metabolic syndrome on mortality in patients with non-alcoholic and alcohol-related fatty liver disease.Clin Gastroenterol Hepatol. 2019; 17: 162-1633Abstract Full Text Full Text PDF Scopus (48) Google Scholar Although the interaction may not be linear, it is present even among mild and moderate drinkers.17Aberg F. Helenius-Hietala J. Puukka P. et al.Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population.Hepatology. 2018; 67: 2141-2149Crossref PubMed Scopus (89) Google Scholar, 24Hart C.L. Morrison D.S. Batty G.D. et al.Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies.BMJ. 2010; 340: c1240Crossref PubMed Scopus (234) Google Scholar Conversely, obesity and the metabolic syndrome aggravate progression of AFLD, and increase the incidence and mortality of hepatocellular carcinoma, likely as a result of synergistic injury from nonalcoholic steatohepatitis.25Chiang D.J. McCullough A.J. The impact of obesity and metabolic syndrome on alcoholic liver disease.Clin Liver Dis. 2014; 18: 157Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar In light of this accumulating data, it seems that it is time to revise our definition and nomenclature for AFLD and NAFLD. Based on current evidence, one could argue that the conventional threshold of alcohol consumption for a diagnosis of NAFLD should be updated to zero or near to zero. In reality, this would be impractical for a multitude of reasons, including but not limited to the high prevalence of both conditions, their overlapping features, and the methodologic challenges in assessing alcohol consumption in individuals with NAFLD. In particular, there is no questionnaire that has the ability to exclude alcohol consumption to zero or close to zero levels, and the episodic nature of usual alcohol use renders blood testing problematic. In addition, questionnaires usually document current drinking patterns and are less accurate or able to assess prior consumption and lifetime drinking history, not the least because of recall bias. There is also marked variation in defining related terms, as for example what is “social drinking”? Finally, in clinical practice, physicians do not have the luxury of time for truly detailed histories of alcohol ingestion. Given these considerations, perhaps it is time for clinicians to recognize that, within the spectrum of fatty liver disease, there will be patients with true alcohol-related liver disease (AFLD), those with predominant AFLD compounded by metabolic cofactors, those with true NAFLD in whom alcohol consumption is near zero and disease progression is due to metabolic factors, and perhaps a majority with fatty liver disease owing to an abnormal metabolic milieu but with alcohol intake of ≤30 g/d. The latter group, currently encompassed by the term NAFLD, could not truly be defined as having NAFLD with no contribution from alcohol, nor does the term recognize the existence of systemic metabolic dysfunction in these patients. An alternative would be to eliminate the term NAFLD from the lexicon and use a term that better reflects the clinical phenotype. Clearly there is a need, and this articles is a call to update the current nomenclature for fatty liver diseases, by international consensus. Such consensus should develop appropriate terminology that reflects pure metabolic dysfunction predominant fatty liver (MPFL) and alcohol predominant fatty liver (APFL; or steatohepatitis from either entity) at either ends of the spectrum. Many, if not most, patients will have liver disease with overlap contributions from both metabolic dysfunction and from alcohol; their clinical course, progression, and outcomes are likely very different from those at either end of the spectrum. Patients with metabolic dysfunction predominant fatty liver, for example, could be further stratified according to alcohol use. Similarly, patients with alcohol predominant fatty liver could be stratified according to the presence of coexisting metabolic features (Figure 1). This we suggest is more than an issue of semantics and nomenclature; without more precise use of terms to define fatty liver diseases, neither science nor patient care can be optimal. To improve consistency for future research, assessment of drugs in clinical trials, and public health initiatives, coordinated action by consensus is required, which is not solely for the academic purist. In conclusion, with the increased global prevalence of fatty liver disease, efforts are underway to further characterize and subphenotype the disease as a necessary tool for the design of clinical trials and for patient stratification. With accumulating evidence that the safe limit for alcohol is zero, we are beginning to recognize the influence of many patterns of modest amounts of alcohol on liver disease. Until evidence points to a specific diagnostic test rather than merely exclusion criteria for diagnosis, we are calling for a consensus to develop a more appropriate nomenclature.