Non-alcoholic fatty liver disease: a pandemic disease with multisystem burden
Editorial

Non-alcoholic fatty liver disease: a pandemic disease with multisystem burden

Somaya Albhaisi1, Danny Issa2, Naim Alkhouri3

1The Division of Internal Medicine, 2The Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA; 3The Texas Liver Institute, University of Texas (UT) Health San Antonio, San Antonio, TX, USA

Correspondence to: Naim Alkhouri, MD. Director of the Texas Metabolic Center, Texas Liver Institute, 607 Camden Street, San Antonio, TX, USA. Email: Alkhouri@txliver.com.

Provenance: This is an invited Editorial commissioned by Editor-in-Chief Yilei Mao (Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China).

Comment on: Adams LA, Anstee QM, Tilg H, et al. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 2017;66:1138-53.


Submitted Apr 28, 2018. Accepted for publication Jul 03, 2018.

doi: 10.21037/hbsn.2018.07.01


Non-alcoholic fatty liver disease (NAFLD) is a leading cause of liver-related morbidity and mortality in the United States and globally (1,2). A large body of literature currently exists to suggest at the clinical burden of NAFLD is not only confined to liver but may rather represent a major part of a multisystem disease (3). Along with the well-known association with metabolic syndrome (MetS), NAFLD has proven to strongly correlate with cardiovascular disease (CVD), chronic kidney disease (CKD), type 2 diabetes (T2D) and potentially osteoporosis and extra-hepatic malignancies (4,5).

Over the last decade, remarkable advances have been made in the understanding of the pathophysiology of NAFLD (6,7). However, the exact mechanism of hepatic fat accumulation and the progression to nonalcoholic steatohepatitis (NASH), the more severe form of the disease, is only partially elucidated. NAFLD progresses when hepatic lipid accumulation overcomes the combination of intra-hepatic lipid oxidation and lipid export (8,9). Emerging evidence shows that hepatic fat is essentially the primary ectopic fat driving the formation of visceral adipose tissue (VAT) (8,10). Furthermore, multiple cross-sectional studies link liver fat and VAT with other metabolic complications of obesity, including insulin resistance, T2D, and even CVD (11,12).

In their recent article, Adams and colleagues examine the magnitude of the associations between NAFLD and several extra-hepatic conditions. In this comprehensive review of the literature, the authors focus on the epidemiologic data and clinical implications of NAFLD as a manifestation of multi-systemic disease (13).

The association that carries the most significant clinical relevance is the one between NAFLD and CVD, which has been the focus of multiple studies recently. A strong association between NAFLD and several markers of subclinical atherosclerosis was reported by a meta-analysis of multiple cross-sectional studies. Those markers included increased carotid intima-media thickness, increased coronary artery calcification, impaired flow-mediated vasodilation and arterial stiffness. This association was independent of the classical CVD risk factors (14). Moon et al. reported a significant and independent association between NAFLD and carotid artery inflammation through a cohort of healthy adult men, using 18F-fluorodeoxyglucose positron emission tomography (15).

In recent years, there has been abundant evidence on the potential links between NAFLD and impaired kidney function. An increased incidence of CKD in patients with NAFLD was found by the Valpolicella Heart Diabetes Study which followed patients with T2D who had normal kidney function over a period of 6 years (16). This was supported by another retrospective study on a cohort of non-diabetic, non-hypertensive men with normal kidney function. The study revealed that NAFLD was associated with increased incidence of CKD, independent of age, sex, and other factors (17). Additionally, studies have shown that NAFLD is a risk factor for developing CKD after liver transplant (18). An article by Houlihan et al. demonstrated that approximately 30% of patients with NASH progress to stage III CKD compared to 8% of non-NASH patients two years after liver transplantation (19).

NAFLD is strongly associated with insulin resistance and T2D. Ballestri et al. conducted a study of a large population of patients from 20 prospective studies and found that the presence of NAFLD (diagnosed by enzyme levels or US) was associated with 1.6–2.0-fold increase in the risk of developing T2D (20). Another example is a similar study which revealed that the presence of NAFLD increased the incidence of MetS (17).

NAFLD was found to be associated with increased incidence of colorectal adenomas in a large Korean study by Hwang et al. (21) Same results were revealed by a cross-sectional study, in addition to the association with high risk of colorectal neoplasm (22).

Malignancies are the second most common cause of death among NAFLD patients. They include both gastrointestinal and extra-intestinal cancers. Fatty liver significantly increased all-cancers risk based on the Danish Study. Obesity is believed to play the major role in predisposing to cancers per a recent review (23). NAFLD and its parallel extra-hepatic conditions are emerging as one very common and progressive multi-systemic disease. The impaired hepatic functions in patients with NAFLD may actually be the primary driver for this expansive multi -systemic process. Cardiac events and extra-hepatic malignancy are not only more common in NAFLD patients, but also the leading causes for death in this patient population. CKD and T2D incident and prevalence are also higher in fatty liver patients, but they tend to improve with the improvement/resolution of NAFLD; a very strong argument that liver fat is the main trigger in this process. It is of extreme significance to raise awareness of these associations in order to initiate the appropriate screening methods and apply early medical interventions necessary to improve long-term outcomes and prevent complications in patients with NAFLD.


Acknowledgements

None.


Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.


References

  1. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol 2015;62:S47-64. [Crossref] [PubMed]
  2. Lonardo A, Nascimbeni F, Maurantonio M, et al. Nonalcoholic fatty liver disease: Evolving paradigms. World J Gastroenterol 2017;23:6571-92. [Crossref] [PubMed]
  3. Armstrong MJ, Adams LA, Canbay A, et al. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 2014;59:1174-97. [Crossref] [PubMed]
  4. Musso G, Gambino R, Cassader M, et al. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011;43:617-49. [Crossref] [PubMed]
  5. Musso G, Gambino R, Tabibian JH, et al. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med 2014;11. [Crossref] [PubMed]
  6. Arab JP, Arrese M, Trauner M. Recent Insights into the Pathogenesis of Nonalcoholic Fatty Liver Disease. Annu Rev Pathol 2018;13:321-50. [Crossref] [PubMed]
  7. Lonardo A, Targher G. NAFLD: Is There Anything New under the Sun? Int J Mol Sci 2017;18. [Crossref] [PubMed]
  8. Liu Q, Bengmark S, Qu S. The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD). Lipids Health Dis 2010;9:42. [Crossref] [PubMed]
  9. Fotbolcu H, Zorlu E. Nonalcoholic fatty liver disease as a multi-systemic disease. World J Gastroenterol 2016;22:4079-90. [Crossref] [PubMed]
  10. Lee JJ, Pedley A, Hoffmann U, et al. Visceral and Intrahepatic Fat Are Associated with Cardiometabolic Risk Factors Above Other Ectopic Fat Depots: The Framingham Heart Study. Am J Med 2018;131:684-92.e12. [Crossref] [PubMed]
  11. du Plessis J, van Pelt J, Korf H, et al. Association of Adipose Tissue Inflammation With Histologic Severity of Nonalcoholic Fatty Liver Disease. Gastroenterology 2015;149:635-48.e14. [Crossref] [PubMed]
  12. Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 2014;15:6184-223. [Crossref] [PubMed]
  13. Adams LA, Anstee QM, Tilg H, et al. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 2017;66:1138-53. [Crossref] [PubMed]
  14. Oni ET, Agatston AS, Blaha MJ, et al. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? Atherosclerosis 2013;230:258-67. [Crossref] [PubMed]
  15. Moon SH, Noh TS, Cho YS, et al. Association between nonalcoholic fatty liver disease and carotid artery inflammation evaluated by 18F-fluorodeoxyglucose positron emission tomography. Angiology 2015;66:472-80. [Crossref] [PubMed]
  16. Targher G, Byrne CD. Non-alcoholic fatty liver disease: an emerging driving force in chronic kidney disease. Nat Rev Nephrol 2017;13:297-310. [Crossref] [PubMed]
  17. Marcuccilli M, Chonchol M. NAFLD and Chronic Kidney Disease. Int J Mol Sci 2016;17:562. [Crossref] [PubMed]
  18. Mikolasevic I, Filipec-Kanizaj T, Mijic M, et al. Nonalcoholic fatty liver disease and liver transplantation - Where do we stand? World J Gastroenterol 2018;24:1491-506. [Crossref] [PubMed]
  19. Houlihan DD, Armstrong MJ, Davidov Y, et al. Renal function in patients undergoing transplantation for nonalcoholic steatohepatitis cirrhosis: time to reconsider immunosuppression regimens? Liver Transpl 2011;17:1292-8. [Crossref] [PubMed]
  20. Ballestri S, Zona S, Targher G, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol 2016;31:936-44. [Crossref] [PubMed]
  21. Hwang ST, Cho YK, Park JH, et al. Relationship of non-alcoholic fatty liver disease to colorectal adenomatous polyps. J Gastroenterol Hepatol 2010;25:562-7. [Crossref] [PubMed]
  22. Wong VW, Wong GL, Tsang SW, et al. High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis. Gut 2011;60:829-36. [Crossref] [PubMed]
  23. Steele CB, Thomas CC, Henley SJ, et al. Vital Signs: Trends in Incidence of Cancers Associated with Overweight and Obesity - United States, 2005-2014. MMWR Morb Mortal Wkly Rep 2017;66:1052-8. [Crossref] [PubMed]
Cite this article as: Albhaisi S, Issa D, Alkhouri N. Non-alcoholic fatty liver disease: a pandemic disease with multisystem burden. Hepatobiliary Surg Nutr 2018;7(5):389-391. doi: 10.21037/hbsn.2018.07.01