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Nonalcoholic Fatty Liver Disease: Lessons Learnt in the Last Five Years

Published:August 29, 2020DOI:https://doi.org/10.1016/j.jceh.2020.07.008

      Abbreviations:

      CVD (cardiovascular disease), IL (interleukin), JCEH (Journal of Clinical and Experimental Hepatology), NAFL (nonalcoholic fatty liver), NAFLD (nonalcoholic fatty liver disease), NASH (nonalcoholic steatohepatitis), PPAR (peroxisome proliferator–activated receptor)
      Nonalcoholic fatty liver disease (NAFLD), associated with a sedentary lifestyle and the modern diet containing excessive calories, saturated fat, and refined carbohydrates, is now a global health epidemic and is replacing viral hepatitis and ethanol as one of the most common causes of chronic liver disease. The disease affects around 25% of the general population globally, and approximately 100 million people are affected with this condition in the United States alone. Recent data suggest that prevalence of NAFLD is almost the same in Asia as in the West. Prevalence of NAFLD among the general population in India varies from 9% to 53%, with higher prevalence in urban areas and in those with metabolic risk factors. Special populations with overweight/obesity, diabetes mellitus, metabolic syndrome, hypothyroidism, and polycystic ovarian syndrome and those with unexplained rise in transaminase levels, cryptogenic cirrhosis, and hepatocellular carcinoma (HCC) have higher prevalence of NAFLD than that seen in the general population.
      We are gaining insight into the pathogenesis, spectrum of disease, diagnostic methods, and new drug targets, which make the study of NAFLD one of the most evolving fields in liver disease. NAFLD may progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma in a significant proportion of affected individuals. Recent data from India suggest that a large number of patients with NAFLD at presentation have significant liver disease owing to the presence of hepatic inflammation and fibrosis and that NAFLD is an important cause of cryptogenic cirrhosis and HCC.
      The Journal of Clinical and Experimental Hepatology (JCEH) Editorial Board has selected a series of review articles on NAFLD published in this journal over the last 5 years and compiled them for this virtual supplement on NAFLD. The articles selected for this virtual supplement were rigorously peer reviewed before publication in the JCEH and have been compiled in this virtual supplement to provide a single consolidated document on the available literature of NAFLD.

      Epidemiology

      In this series of review articles, Ching-Yeung Yu et al.
      • Ching-Yeung Yu B.
      • Kwok D.
      • Wong V.W.
      Magnitude of non-alcoholic fatty liver disease: eastern perspective.
      and Samji et al.
      • Samji N.S.
      • Verma R.
      • Satapathy S.K.
      Magnitude of non-alcoholic fatty liver disease: western perspective.
      describe the epidemiology of NAFLD with perspectives from the East and West, respectively. Epidemiological data from both the Eastern and Western world suggest that both incidence and prevalence of NAFLD are increasing and are related to the changing lifestyle and the increasing prevalence of obesity, diabetes mellitus, and metabolic syndrome. In addition to the environmental factors, genetic factors probably also play a role in the inter-racial differences in the prevalence of NAFLD.

      Pathogenesis

      Pathogenesis of NAFLD and its associated complications is poorly understood. A better understanding of molecular pathogenesis is essential for more effective preventive and therapeutic interventions. Iyer et al.
      • Iyer S.
      • Upadhyay P.K.
      • Majumdar S.S.
      • Nagarajan P.
      Animal Models correlating Immune cells for the development of NAFLD/NASH.
      in their review shed light on animal models for the study of NAFLD. Although basic differences between animal and human NAFLD remain, animal models have helped a lot in understanding the pathogenesis and role of various therapeutic molecules in human NAFLD.
      Both environmental and genetic factors are involved in the pathogenesis of NAFLD. The sedentary lifestyle and calorie-rich food lead to weight gain, insulin resistance, and metabolic syndrome, which is the main pathogenic mechanism for NAFLD. Metabolic risk factors such as type 2 diabetes mellitus not only increase the prevalence of NAFLD but also are responsible for increased severity of the disease. In fact, a bidirectional link between NAFLD, diabetes mellitus, and metabolic syndrome has been established, and patients with NAFLD are at increased risk of developing diabetes mellitus and metabolic syndrome in the long term. In the review article of Bedi et al.,
      • Bedi O.
      • Aggarwal S.
      • Trehanpati N.
      • Ramakrishna G.
      • Krishan P.
      Molecular and pathological events involved in the pathogenesis of diabetes associated non-alcoholic fatty liver disease.
      they elucidate the molecular pathogenesis of diabetes-associated NAFLD via hepatic insulin resistance and hyperglycemia, oxidative stress, intestinal dysbiosis, elevated levels of fetuin-A, adipokines including leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, and retinol binding protein 4 (RBP4), and inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL) 1β, and so on.
      Kovalic et al.
      • Kovalic A.J.
      • Banerjee P.
      • Tran Q.T.
      • Singal A.K.
      • Satapathy S.K.
      Genetic and epigenetic culprits in the pathogenesis of nonalcoholic fatty liver disease.
      reviewed the genetic and epigenetic control on the development of NAFLD. The development of the genome-wide association study technology has allowed the identification of numerous genetic polymorphisms in NASH (e.g., PNPLA3, MBOAT7, APOB, TM6SF2, IL-28B, SOD2). Data suggest that the PNPLA3 gene variant not only is responsible for interindividal and interethnic differences in prevalence but also plays an important role in the severity of the disease and patients with PNPLA3 rs738409 (G allele) being at higher risk of having raised alanine transaminase (ALT) levels, NASH, NASH with fibrosis, and HCC. The authors in the review article also provide data regarding the epigenetic changes (histone modifications, DNA methylation, microRNAs, and so on), which interact with inherited risk factors to determine an individual's susceptibility to NASH.
      • Kovalic A.J.
      • Banerjee P.
      • Tran Q.T.
      • Singal A.K.
      • Satapathy S.K.
      Genetic and epigenetic culprits in the pathogenesis of nonalcoholic fatty liver disease.

      Spectrum

      The spectrum of NAFLD ranges from nonalcoholic fatty liver (NAFL) or simple steatosis to NASH, which has higher propensity to progress on to NASH-related cirrhosis and HCC. In two separate articles in this issue, De and Duseja
      • De A.
      • Duseja A.
      Natural History of Simple Steatosis or Non-alcoholic Fatty Liver (NAFL).
      and Sharma et al.
      • Sharma M.
      • Mitnala S.
      • Vishnubhotla R.K.
      • Mukherjee R.
      • Reddy D.N.
      • Rao P.N.
      The riddle of Nonalcoholic fatty liver disease: progression from NAFL to NASH.
      describe the natural history of NAFL and NASH. Both the articles provide data that suggest that simple steatosis is not that “simple” and can progress to NASH with or without fibrosis especially with the worsening metabolic abnormalities. The severity of disease at presentation would also be particularly important in determining the progression of the disease. However, those presenting with NAFL have slower risk of progression to advanced fibrosis than those presenting with NASH. Hence, the distinction between NAFL and NASH is important at baseline, and this aspect has been very well highlighted in these two articles in this issue.
      • De A.
      • Duseja A.
      Natural History of Simple Steatosis or Non-alcoholic Fatty Liver (NAFL).
      ,
      • Sharma M.
      • Mitnala S.
      • Vishnubhotla R.K.
      • Mukherjee R.
      • Reddy D.N.
      • Rao P.N.
      The riddle of Nonalcoholic fatty liver disease: progression from NAFL to NASH.
      Recent data suggest that HCC can occur in patients with NAFL/NASH without the presence of high fibrosis or cirrhosis. Although the guidelines for screening and surveillance for HCC in patients with cirrhosis are available, there are no recommendations regarding the screening for HCC in patients with noncirrhotic NAFLD. Given the high prevalence of NAFLD in the community, regular screening for HCC in these patients looks impractical as well. Acharya
      • Acharya S.
      Hepatocellular Carcinoma Screening and NAFLD: How Is it Different?.
       in his review article discusses in detail regarding the screening for HCC in patients with NAFLD.
      Other than the factors discussed earlier, age is another important determinant of the severity of the disease, and in general, older patients are more likely to have severe disease (NASH with or without advanced fibrosis) than children and young adults. But because of the changing lifestyle, prevalence of NAFLD is increasing widely in children as well. However, there are some differences between children and adult patients with NAFLD. This aspect has been reviewed very well by Fitzpatrick and Dhawan
      • Fitzpatrick S.E.
      • Dhawan A.
      Childhood and adolescent NAFLD: is it different from adults?.
      in this issue. Data reviewed by them suggest that NAFLD now affects 10–20% of the general pediatric population, with the mean age of presentation between 10 and 13 years. And within the next 10 years, it is expected to become the leading cause of liver pathology as well as liver failure and indication for liver transplantation in childhood and adolescents in the Western world.

      Extrahepatic Associations

      Tariq et al.
      • Tariq R.
      • Axley P.
      • Singal A.K.
      Extra-hepatic manifestations of non-alcoholic fatty liver disease: a review.
      in their review, in this issue, comprehensively explain the extrahepatic manifestations of NAFLD including cardiovascular disease (CVD), type 2 diabetes mellitus, chronic kidney disease, malignancy especially colorectal cancer, pulmonary disorders including obstructive sleep apnea, endocrine disorders such as hypothyroidism and polycystic ovarian syndrome, dermatological disorders especially psoriasis, and hematological associations including iron overload and susceptibility to thrombosis. The most common cause of death in patients with NAFLD is CVD rather than liver disease. This is because of the association of NAFLD with metabolic syndrome and the cytokine milieu, which puts patients with NAFLD to a higher risk of CVD. In comparison with those with NASH, patients with NASH are more commonly associated with systemic disorders and CVD. Hence, even when asymptomatic, it is very important to decide if patients with NAFLD need to be screened for CVD. This decision is even more important in patients with NASH-related cirrhosis being evaluated for liver transplantation. Choudhury and Duseja
      • Choudhary N.S.
      • Duseja A.
      Screening of cardiovascular disease in non-alcoholic fatty liver disease: whom and how?.
      in their review article, in this issue, not only explain the link between NAFLD and CVD, diastolic dysfunction, impaired ventricular relaxation, increased myocardial thickness, and reduced exercise tolerance but also give clear guidelines as to whom, when, and how to screen patients with NAFLD for CVD.

      Diagnosis

      As mentioned earlier, the distinction between NAFL and NASH is very important not only for the point of prognosis but also for deciding treatment modalities, pharmacotherapy usually preserved for patients with NASH. Although the gold standard for distinguishing NAFL and NASH is still liver histology, it is not possible to subject all patients with NAFLD to liver biopsy. Hence, a thorough noninvasive assessment is very important for the prediction of severe liver disease and suggesting a liver biopsy. Singh and Barik
      • Singh S.P.
      • Barik R.K.
      Non-invasive biomarkers in non-alcoholic fatty liver disease - are we there yet ?.
      have very elegantly reviewed the subject on the noninvasive diagnosis of NAFLD with currently available imaging and scores.

      Treatment

      Lifestyle interventions remain the main treatment for patients with NAFLD. Lifestyle interventions include control of metabolic risk factors and weight reduction for those with overweight and obesity. The amount of weight reduction usually depends on the severity of underlying liver disease and is usually achieved by creating a negative balance between energy intake and expenditure with the combination of regular exercise and dietary modifications. Eapen

      Eapen, C.E., What are the current pharmacological therapies for NAFLD?

      in his review article discusses in detail about the current management of patients with NAFLD with focus on lifestyle interventions. In another review article, Mahady and George
      • Mahady S.E.
      • George J.
      The future liver of the Asia Pacific: fatter and firmer from more fructose and fortune?.
      covered the diet and lifestyle interventions for patients with NAFLD pertinent to Asia.
      Pharmacotherapy in patients with NAFLD is usually limited to patients with biopsy-proven NASH and includes the use of pioglitazone and vitamin E. Although not approved by the Food and Drug Administration, USA (FDA), most of the scientific societies do recommend the use of pioglitazone and vitamin E in NASH based on the available literature. A recent addition for the treatment of NASH in India is the dual peroxisome proliferator–activated receptor (PPAR) alpha/gamma agonist called saroglitazar, which has been recently approved by the Drugs Controller General of India for use in patients with NASH with F1-3 fibrosis. Choudhary et al.
      • Choudhary N.S.
      • Kumar N.
      • Duseja A.
      Peroxisome proliferator-activated receptors and their agonists in non-alcoholic fatty liver disease (NAFLD).
      in their review article discuss in detail about different PPARs and their natural and synthetic ligands including the dual PPAR and pan-PPAR agonists. In addition to the recommended drugs, there are a lot of other available drugs that have been used in patients with NASH but are not recommended because of the lack of histological efficacy. One such class of drugs is the antidiabetic drugs. Kothari et al.
      • Kothari S.
      • Dhami-Shah H.
      • Shah S.R.
      Anti-diabetic drugs and statins in NAFLD.
      in their review article discuss the evidence-based role of antidiabetic drugs (pioglitazone, liraglutide, gliptins, metformin, SGLT2 inhibitors, and so on) and statins in the management of NASH.
      A lot of new drugs for the treatment of NASH are being evaluated in phase II or phase III clinical trials, and there have been some recent successes and failures. Targets for new drugs include metabolic pathways or the anti-inflammatory or antifibrotic actions. In addition to monotherapy, different combinations of drugs are also being evaluated for the treatment of NASH. Overall, drug development in NASH is an evolving and exciting field and may provide some cure for patients with NASH in the near future. Thiagarajan and Aithal
      • Thiagarajan P.
      • Aithal G.P.
      Drug development for NAFLD: landscape and challenges.
      in their review article describe the current drug development models for NASH and give insight into this challenging field.
      Except for some special issues, the treatment of patients with NASH-related cirrhosis and HCC is largely the same as for other indications. But for special focus on obesity, diabetes mellitus, and cardiac and kidney disease, the indications for liver transplantation for NASH-related cirrhosis and HCC also remain the same as for other etiologies. The recurrence of NAFLD in patients who underwent liver transplant is almost universal in those with NASH or cryptogenic cirrhosis, although it can occur de novo in patients subjected to liver transplantation for other indications. The perioperative challenges of patients with NAFLD undergoing liver transplantation and new onset of NAFLD after surgery are discussed in the review by Choudhary and Saigal.
      • Choudhary N.S.
      • Saigal S.
      Preventive strategies for NAFLD after liver transplantation.

      Recommendations

      Because of the high prevalence of NAFLD in the general and special population, a stepwise approach is usually recommended in the management of such patients. The evaluation of patients with NAFLD usually takes into account the age, history of alcohol, presence of metabolic risk factors, exclusion of other causes of hepatic steatosis, and raised levels of transaminases if present. Finally, the severity of liver disease is assessed noninvasively and if required by liver biopsy. In addition to lifestyle interventions, which are recommended to all, pharmacotherapy is usually given to patients with NASH. The management of patients with NAFLD is also dependent on the availability of resources and expertise and may vary from country to country and between different centers. To frame the guidelines for managing patients with NAFLD and metabolic syndrome in India, the Indian National Association for Study of the Liver in collaboration with the Endocrine Society of India, Indian College of Cardiology, and the Indian Society of Gastroenterology had come out with a position paper and has been included in this virtual supplement.
      • 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.
      We are confident that this issue of the JCEH will be of benefit for all students, researchers, and clinicians in the field of internal medicine, hepatology, and gastroenterology and hope it provokes more work in the rapidly changing and challenging management of NAFLD.

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