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Introductory Chapter: Nonalcoholic Fatty Liver Disease - What Should We Know?

Written By

Emad Hamdy Gad and Yasmin Kamel

Submitted: June 11th, 2019 Published: November 20th, 2019

DOI: 10.5772/intechopen.88041

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1. Introduction

Nonalcoholic fatty liver disease (NAFLD) is considered a major challenge because of its prevalence, difficulties in diagnosis, complex pathogenesis, and lack of approved therapies. It will become the main cause of chronic liver disease in adults and children and the leading indication for liver transplantation (LT) in the next decades replacing hepatitis C virus (HCV) infection [1]. It is characterized by excessive hepatic fat accumulation, associated with insulin resistance (IR), where liver pathology shows steatosis in >5% of hepatocytes or a proton density fat fraction >5.6% assessed by proton magnetic resonance spectroscopy (1HMRS) or quantitative fat/water selective magnetic resonance imaging (MRI) [2]. It represents a group of conditions ranging from simple asymptomatic liver steatosis (nonalcoholic fatty liver (NAFL)) (known by imaging or histology) to cirrhosis (nonalcoholic steatohepatitis (NASH) or cryptogenic), end stage liver disease (ESLD), and hepatocellular carcinoma (HCC), passing through nonalcoholic steatohepatitis (NASH), which is characterized by the presence of apoptosis, ballooning, inflammation, and fibrosis with the absence of secondary causes of hepatic fat accumulation such as significant alcohol consumption or viral infection [3]. In the majority of patients, NAFLD is commonly associated with metabolic comorbidities such as obesity, type 2 DM (T2DM), and dyslipidemia. So it became common after increased prevalence of these comorbidities [4].

Our book discusses some new topics related to NAFLD, where we divided it into four sectors: the first sector includes introductory chapter about NAFLD; the second sector contains experimental work related to the disease, while the third sector discusses diseases related to NAFLD; and finally the fourth sector includes a new noninvasive tool to diagnose NAFLD. The book gives hints regarding NAFLD prevalence, etiology, pathogenesis, pathology, diagnosis, and treatment.

This introductory chapter discusses the recent updated data on the prevalence, natural history, pathophysiology, pathology, diagnosis, and treatment of the disease.

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2. Natural history and disease progression

NAFLD prevalence in general population ranges between 13.48 and 31.79% differing according to diagnostic method, age, sex, and ethnicity [5, 6], while NASH prevalence in the general population ranges between 1.5 and 6.45% [5]. It is a slowly progressive disease [7]. Patients with histological NASH, especially those with some degree of fibrosis, are at higher risk for disease progression and adverse outcomes such as decompensated cirrhosis, HCC, LT, or liver-related mortality [5, 8].

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3. Pathogenesis

NAFLD is tightly associated with IR not only in the liver but also in muscle and adipose tissues and also with metabolic syndrome (MetS), defined as the cluster of any three of the following five features associated with IR: impaired fasting glucose (IFG) or T2DM, hypertriglyceridemia, low high-density lipoprotein (HDL), increased waist circumference (WC), and high blood pressure. So, the presence of MetS in any given patient should lead to an evaluation of the risk of NAFLD and vice versa [9].

A high-calorie diet, saturated fats, and a high fructose intake have been associated with obesity and NAFLD [10]. It is documented that visceral obesity is one of NASH predictors; it is associated with insulin resistance, oxidative stress, inflammatory cascade, and overflow of portal triglycerides [11, 12]. So, follow-up of the disease and its progression is mandatory in obese persons.

T2DM is associated with NAFLD severity, NASH development, advanced fibrosis, and HCC [13]. It is also related to IR, obesity, dyslipedemia, and elevated liver enzymes [14].

Recently, multiple parallel hits are responsible for NAFLD pathogenesis and progression (i.e., impaired mitochondrial adenosine triphosphate (ATP) activity [15], depletion of mitochondrial glutathione [16, 17], hypoxia associated with impaired blood flow or obesity-related obstructive sleep apnea [18], dysregulated adipokine production [19], the effects of a high fructose diet [20], and rapid weight loss [21]).

However, hepatic iron is a source of oxidative stress and hepatocyte dysfunction; its role in NAFLD and NASH remains controversial [22].

Both animal and human studies support the concept that the hepatocellular injury in NAFL persons that lead to NASH is caused by overload of primary metabolic substrates (glucose, fructose, and fatty acids) in the liver, resulting in diversion of fatty acids into pathways that promote cellular injury and dysfunctional response to that injury [23, 24].

In human models and in the setting of established IR and a diet high in saturated fats, hepatic traffic of excess free fatty acids (FFA) induces hepatocyte injury via lipotoxicity, caused by oxidative stress through the generation of lipotoxic metabolites (such as ceramides, diacylglycerols, and lysophosphatidyl choline) and reactive oxygen species (ROS) [25]. However, in animal models, the oxidative stress that occurs in the setting of obesity-related IR and lipotoxicity is central to hepatocyte injury and is critical to the pathogenesis of NASH [26].

It is documented that lipotoxicity leads to hepatic cell injury and death, via apoptosis and/or necrosis, and this is an important driver of inflammation, NASH, and fibrosis [27, 28]. Oxidative stress is a major driver of hepatocyte senescence that represents a cellular stress response and an irreversible cell cycle arrest aimed to limit the proliferation of damaged cells and subsequent tumor development. Furthermore, senescent cells can mediate NAFLD progression via the active secretion of pro-inflammatory factors that affect the microenvironment, and this represents the adoption of a “senescence-associated secretory phenotype” (SASP) [26]. In NASH, the inflammatory response includes both the innate and adaptive immunity; the cascade begins with hepatocyte injury in the setting of IR and lipotoxicity and is propagated by cellular apoptosis, culminating with the activation of hepatic stellate cells (HSCs) and ensuing fibrosis [26].

In short, the pathogenesis of NASH goes as follows: Hepatocytes are affected by lifestyle factors as a high saturated fatty acid (SFA) diet, obesity, IR, and hepatic steatosis; these multiple parallel metabolic hits lead to cellular damage, via a process called “lipotoxicity,” involving excessive oxidative stress principally driven by the lipotoxic metabolites of SFA. Injured hepatocytes release damage-associated metabolic patterns (DAMPs) that initiate an inflammatory response, predominantly via toll-like receptors (TLRs) and activate pro-inflammatory signaling pathways in the setting of increased adipokine levels. Furthermore, injured hepatocytes undergo necrosis, apoptosis, and senescence that have a great role in disease progression. Direct recruitment of Kupffer cells (KC) and other components of the innate immune response occurs with activation of the inflammasome and the coordinated release of pro-inflammatory and pro-fibrogenic cytokines and ligands (e.g., Hh, OPN). Also, KC promotes a pro-inflammatory microenvironment that initiates adaptive immune response. HSC are subsequently activated to produce extracellular matrix leading to progressive fibrosis, cirrhosis, and its complications (e.g., HCC). Engulfment of apoptotic bodies and factors produced by senescent cells (SASP) can also influence HSC activity directly [26].

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4. Diagnosis

NAFL encompasses (a) steatosis alone; (b) steatosis with lobular or portal inflammation, without ballooning; or (c) steatosis with ballooning but without inflammation. The diagnosis of NASH requires the joint presence of steatosis, ballooning, and lobular inflammation. So, liver biopsy is essential for its diagnosis [29]. Biopsy should give comment on steatosis severity (mild, moderate, or severe). Specific scoring systems such as NAFLD activity score (NAS) and/or steatosis activity fibrosis (SAF) may be appropriate. Moreover, the presence or absence of fibrosis should be described (stage 1 is zone 3 (perivenular or perisinusoidal fibrosis) or periportal fibrosis, stage 2 is both zone 3 and periportal fibrosis, stage 3 is bridging fibrosis with nodularity, and stage 4 is cirrhosis) [5]. Because of liver biopsy invasive nature, sampling errors, cost, and its related morbidity and mortality and noninvasive tools to detect NAFL and NASH were thoroughly studied and developed. They have the following advantages: (i) identification of the risk of NAFLD in people with high metabolic risk in primary care settings, (ii) identification of those with worse prognosis (i.e., severe NASH) in secondary and tertiary care settings, and (iii) disease progression and therapeutic response monitoring [2]. US, computed tomography (CT), and MRI are noninvasive diagnostic methods of moderate and severe steatosis, and they can provide additional hepatobiliary information; hence, they should be performed as first-line diagnostic tools for steatosis [2]. Moreover, MRI, either by spectroscopy (MRS) or by proton density fat fraction (PDFF), is a good noninvasive tool for quantifying steatosis [5]; furthermore, the best-validated steatosis scores are the fatty liver index (FLI) and the SteatoTest and the NAFLD liver fat score; they variably predict metabolic, hepatic, and cardiovascular outcomes [2]. Regarding NASH, clinical, biochemical, and imaging measures cannot distinguish it from steatosis. However, cytokeratin-18 fragments (CK-18), which are generated during cell death or apoptosis, have modest accuracy for the diagnosis of NASH (66% sensitivity, 82% specificity) [5, 30]. Clinical decision aids (e.g., NAFLD fibrosis score (NFS), FIB-4 index, aspartate aminotransferase [AST] to platelet ratio index [APRI]), serum biomarkers (enhanced liver fibrosis [ELF] panel, fibrometer, FibroTest, and Hepascore), or imaging (e.g., vibration controlled transient elastography (VCTE; FibroScan), MR elastography [MRE], acoustic radiation force impulse imaging, and supersonic shear wave elastography) are acceptable noninvasive procedures for the identification of cases with advanced fibrosis or cirrhosis; furthermore, their combination might confer additional diagnostic accuracy, and monitor disease progression, saving a number of diagnostic liver biopsies [5].

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5. Treatment

It is considered that NAFLD treatments are limited; as the pathogenesis of NASH (as discussed above) involves the complex interaction of cellular responses to chronic injury, furthermore, the development of the disease over many years cannot be easily repaired with short-term intervention (most updated studies have involved short-term treatment only); moreover, NAFLD is thought to be a heterogeneous disease [26]. The management of NAFLD should consist of treating liver disease as well as the associated metabolic comorbidities such as obesity, hyperlipidemia, IR, and T2DM [5].

NAFLD can be treated with lifestyle changes (i.e., healthy diet and habitual physical activity) as weight loss results in improvement of liver enzymes and histology (steatosis, hepatocyte ballooning, and necroinflammtion) and healthy diet improves IR; moreover, both aerobic exercise and resistance training reduce liver fat with no need for drug therapy if there is no NASH or fibrosis [31, 32]. However, successful treatment of NASH should improve outcomes, i.e., decrease NASH-related mortality, and reduce progression to cirrhosis or HCC [2]; this can be achieved with drug therapy that is indicated for progressive NASH (bridging fibrosis and cirrhosis), for early-stage NASH with increased risk of fibrosis progression (age > 50 years; diabetes, MetS, increased ALT) [33], and for active NASH with high necro-inflammatory activity [34].

The oxidative stress from lipotoxicity has a central role in disease progression, and therefore, the use of antioxidants and other approaches to limit this oxidative stress was considered. In some studies, vitamin E (800 IU/day) as an antioxidant improved steatosis, inflammation, and ballooning and induced resolution of NASH [35]. It may be used in non-cirrhotic nondiabetic NASH patients, but further studies are needed before making firm recommendations.

Ursodeoxycholic acid (UDCA) has been investigated in several RCTs as a treatment for NASH at different doses for up to 2 years with some biochemical improvement without any histological effect [36, 37, 38]. Recently, a negative correlation was shown between the degree of coffee intake as antioxidant and fibrosis stage in NASH. However, the role of phlebotomy in management of NASH by decreasing hepatic iron overload and its oxidative stress effect is still controversial. On the other hand and despite being under study, newer approaches for managing NASH were developed (pentoxifylline, infliximab, NK inhibitors, STAT3 blockade, and anti-CD3 therapy); they aimed at affecting the intercellular mechanisms that have a role in the pathogenesis of NASH. Also, the use of specific medical therapies that are effective in patients with metabolic comorbidities (e.g., insulin sensitizing agents (pioglitazone), statins, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers) has also been tried in patients with NASH with promising results [26].

Bariatric surgery decreases liver fat and NASH progression by treating obesity, IR, and diabetes; prospective data showed an improvement in histological NASH lesions, including fibrosis [39, 40, 41].

Lastly, LT is an accepted procedure in NASH patients with ESLD, liver failure, or HCC with comparable overall survival to other indications, despite a higher cardiovascular mortality [42, 43].

Finally, I think the book will give readers important knowledge regarding NAFLD.

References

  1. 1. Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC Medicine. 2017;15:45
  2. 2. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO). EASL—EASD—EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. Journal of Hepatology. 2016;64:1388-1402
  3. 3. Fierbinteanu-Braticevici C, Baicus C, Tribus L, Papacocea R. Predictive factors for nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD). Journal of Gastrointestinal and Liver Diseases. 2011;20(2):153-159
  4. 4. Brunt EM, Wong VW, Nobili V, Day CP, Sookoian S, Maher JJ, et al. Nonalcoholic fatty liver disease. Nature Reviews. Disease Primers. 2015;1:15080
  5. 5. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, 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(1):328-357
  6. 6. Vernon G, Baranova A, Younossi ZM. Systematic review: The epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Alimentary Pharmacology & Therapeutics. 2011;34:274-228
  7. 7. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs. nonalcoholic steatohepatitis: A systematic review and meta-analysis of paired-biopsy studies. Clinical Gastroenterology and Hepatology. 2015;13:643-654, e641–e649; quiz e639–e640
  8. 8. Goh GB, McCullough AJ. Natural history of nonalcoholic fatty liver disease. Digestive Diseases and Sciences. 2016;61:1226-1233
  9. 9. Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A. Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients. 2013;5:1544-1560
  10. 10. Barrera F, George J. The role of diet and nutritional intervention for the management of patients with NAFLD. Clinics in Liver Disease. 2014;18:91-112
  11. 11. Tarantino G, Saldalamacchia G, Conca P, Arena A. Non-alcoholic fatty liver disease: Further expression of the metabolic syndrome. Journal of Gastroenterology and Hepatology. 2007;22:293-303
  12. 12. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Seminars in Liver Disease. 2008;28:370-379
  13. 13. Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology. 2012;56:943-951
  14. 14. Ghouri N, Preiss D, Sattar N. Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: A narrative review and clinical perspective of prospective data. Hepatology. 2010;52:1156-1161
  15. 15. Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: A pilot study. JAMA. 1999;282:1659-1664
  16. 16. Mari M, Caballero F, Colell A, Morales A, Caballeria J, Fernandez A, et al. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metabolism. 2006;4:185-198
  17. 17. Mari M, Colell A, Morales A, Caballero F, Moles A, Fernandez A, et al. Mechanism of mitochondrial glutathione-dependent hepatocellular susceptibility to TNF despite NF-kappa B activation. Gastroenterology. 2008;134:1507-1520
  18. 18. Polotsky VY, Patil SP, Savransky V, Laffan A, Fonti S, Frame LA, et al. Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity. American Journal of Respiratory and Critical Care Medicine. 2009;179:228-234
  19. 19. Musso G, Gambino R, de Michieli F, Durazzo M, Pagano G, Cassader M. Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: Possible pathogenetic role in NASH. Hepatology. 2008;47:1167-1177
  20. 20. Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1961-1971
  21. 21. D’Albuquerque LA, Gonzalez AM, Wahle RC, de Oliveira Souza E, Mancero JM, de Oliveira e Silva A. Liver transplantation for subacute hepatocellular failure due to massive steatohepatitis after bariatric surgery. Liver Transplantation. 2008;14:881-885
  22. 22. O’Brien J, Powell LW. Non-alcoholic fatty liver disease: Is iron relevant? Hepatology International. 2012;6:332-341
  23. 23. Machado MV, Diehl AM. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology. 2016;150:1769-1777
  24. 24. Ertunc ME, Hotamisligil GS. Lipid signaling and lipotoxicity in metabolic inflammation: Indications for metabolic disease pathogenesis and treatment. Journal of Lipid Research. 2016;57:2099-2114
  25. 25. Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites. Hepatology. 2010;52:774-788
  26. 26. Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: Beyond steatosis and inflammation. International Journal of Molecular Sciences. 2014;15:8591-8638
  27. 27. Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacological Reviews. 2008;60:311-357
  28. 28. Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2008;295:G987-G995
  29. 29. Kleiner DE, Brunt EM. Nonalcoholic fatty liver disease: Pathologic patterns and biopsy evaluation in clinical research. Seminars in Liver Disease. 2012;32:3-13
  30. 30. Kwok R, Tse YK, Wong GL, Ha Y, Lee AU, Ngu MC, 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. Alimentary Pharmacology & Therapeutics. 2014;39:254-269
  31. 31. Zelber-Sagi S, Godos J, Salomone F. Lifestyle changes for the treatment of nonalcoholic fatty liver disease: A review of observational studies and intervention trials. Therapeutic Advances in Gastroenterology. 2016;9:392-407
  32. 32. Orci LA, Gariani K, Oldani G, Delaune V, Morel P, Toso C. Exercise-based interventions for nonalcoholic fatty liver disease: A meta-analysis and meta-regression. Clinical Gastroenterology and Hepatology. 2016;14:1398-1411
  33. 33. Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: A longitudinal study of 103 patients with sequential liver biopsies. Journal of Hepatology. 2005;42:132-138
  34. 34. Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: Findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration joint workshop. Hepatology. 2015;61:1392-1405
  35. 35. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. The New England Journal of Medicine. 2010;362:1675-1685
  36. 36. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: Results of a randomized trial. Hepatology. 2004;39:770-778
  37. 37. Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis. Clinical Gastroenterology and Hepatology. 2006;4:1537-1543
  38. 38. Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rossle M, Cordes HJ, et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: A double-blind, randomized, placebo-controlled trial. Hepatology. 2010;52:472-479
  39. 39. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, et al. Bariatric surgery versus intensive medical therapy for diabetes. 3-Year outcomes. The New England Journal of Medicine. 2014;370:2002-2013
  40. 40. Caiazzo R, Lassailly G, Leteurtre E, Baud G, Verkindt H, Raverdy V, et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: A 5-year controlled longitudinal study. Annals of Surgery. 2014;260:893-898
  41. 41. Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric surgery reduces features of non-alcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149:377-388
  42. 42. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141:1249-1253
  43. 43. Wang X, Li J, Riaz DR, Shi G, Liu C, Dai Y. Outcomes of liver transplantation for nonalcoholic steatohepatitis: A systematic review and meta-analysis. Clinical Gastroenterology and Hepatology. 2014;12:e391

Written By

Emad Hamdy Gad and Yasmin Kamel

Submitted: June 11th, 2019 Published: November 20th, 2019