Liver Fat

Defining CMR - Visceral Adipose Tissue: the Culprit? A Marker of Ectopic Fat Deposition?

Key Points

  • Non-alcoholic fatty liver disease is a common cause of chronic liver disease and is closely associated with a range of cardiometabolic risk factors as well as diabetes and mortality risk.
  • It is unknown how liver fat develops but a number of plausible mechanisms have been proposed, including “spillover” of excess energy from adipose tissue, adiponectin deficiency, a high fat diet, and/or overactivation of the endocannabinoid system.
  • Increased liver fat storage is related to hepatic insulin resistance and increased synthesis and secretion of atherogenic lipoproteins.
  • The gold standard method for quantifying liver fat is liver biopsy.
  • However, imaging techniques such as magnetic resonance spectroscopy (MRS) and computed tomography (CT) are safe and reliable alternatives.

Liver Fat: a Marker of Ectopic Fat Deposition

The term ectopic comes from the Greek word ektopos, meaning “out of place.” It has been used to denote fat storage in non-adipose tissue, such as the liver, muscle, pancreas, heart, and others [1]. Recent findings have demonstrated that fat storage in non-adipose tissue causes many of the metabolic complications of obesity [1-3]. Fat storage in the liver is particularly associated with a range of metabolic complications [4-15].

Fatty liver is a key component of non-alcoholic fatty liver disease, a broad condition first described by Leevy et al. [16] in 1962. This disease has symptoms similar to that of alcohol-induced liver damage but is found in non-alcohol abusers. Symptoms are wide-ranging and include fatty infiltration of the liver (hepatic steatosis), fatty infiltration and liver inflammation (non-alcoholic steatohepatitis), and fibrosis and cirrhosis, which can ultimately lead to liver failure.

Non-alcoholic fatty liver disease has emerged as one of the most widespread causes of chronic liver disease [17]. Because of its ability to predict type 2 diabetes risk [18] and its association with various metabolic disturbances [4-15], non-alcoholic fatty liver disease has been proposed as a new potential component of the metabolic syndrome [7].

Epidemiology

Based on increased serum liver enzyme levels, estimates from the third National Health and Nutrition Examination Survey suggest that 6.4 million adults in the United States have non-alcoholic fatty liver disease [19]. As assessed using specialized imaging techniques such as magnetic resonance imaging, fatty liver is found in about 30% of all adults in the United States [20,21]). Non-alcoholic fatty liver disease is much more common in older individuals, with over 30% of adults afflicted [20,21] compared to less than 3% of children [22]. Disease prevalence also varies by sex and is higher among males than females [19,20]. It also varies by race, being highest among Hispanics (45%), followed by Whites (33%), and Blacks (24%) [20]. Roughly half of all diabetics and three-quarters of obese individuals have non-alcoholic fatty liver disease [23,24]. Although liver fat is commonly associated with obesity [25-27], fatty liver can be present in non-obese subjects as well [5,7]. Risk factors for a fatty liver in normal weight individuals include dyslipidemia, insulin resistance, and abdominal obesity [28], all components of the metabolic syndrome.

Liver Fat and Metabolic Diseases

Although originally considered an inconsequential finding, fatty liver has since emerged as a predictor of type 2 diabetes [18] and a potential component of the metabolic syndrome [7]. In fact, it has been documented that non-alcoholic fatty liver disease raises mortality risk [29]. A number of studies have reported that liver fat is linked to health risk factors, including hypertension [30], insulin resistance (4-10), elevated plasma glucose [5,10,11,13,14], elevated insulin [5,8,10,12,15], elevated triglycerides [4,5,7-15], and low levels of HDL cholesterol [5,7,8,12,14]. While the relationship of liver fat to metabolic risk, insulin resistance in particular, is clear, the mechanisms underpinning this relationship are not fully understood.

Pathogenesis

The exact pathophysiology that leads to non-alcoholic fatty liver disease and its metabolic consequences has yet to be defined, although a number of plausible explanations have been proposed. Generally, it has been suggested that adipocyte resistance to the anti-lipolytic effects of insulin [31] and/or the exhaustion of adipose tissue storage capacity [2] increase lipolysis rates and free fatty acid (FFA) delivery to the liver. This “spillover” of lipids from adipose tissue to the non-adipose tissues of the liver eventually exceeds the liver’s ability to secrete fatty acids in the form of VLDL [32], causing liver fat. Excess lipid storage in lean tissues such as the liver can then lead to lipid-induced dysfunction (lipotoxicity) [33] and lipid-induced programmed cell death (lipoapoptosis) [34] (Figure 1). Increased delivery of FFA to the liver, particularly from the visceral depot, may be responsible for hepatic insulin resistance [35], triglyceride accumulation in the hepatocytes [15,36], and increased synthesis and secretion of atherogenic lipoproteins [37].

Lipodystrophy is a rare clinical condition (either acquired or congenital) characterized by selective loss of functional adipose tissue (especially subcutaneous tissue) [38]. This condition severely limits the ability of adipose tissue to store excess energy, which means excess fat is stored in the liver and muscle, leading to insulin resistance and diabetes [39]. To combat this, pharmacological interventions have used thiazolidinediones (TZD), a family of drugs that promote the development of new subcutaneous adipocytes [40] and the expansion of the subcutaneous adipose depot, to decrease liver fat storage [41] and improve insulin sensitivity [42].

Thus, lipids are released into the circulation in proportion to the size of the adipose organ, the large fat mass in obese individuals may also elevate FFA flux to non-adipose tissues in the absence of any abnormality in adipose tissue metabolism [43]. Despite the presence of “functional” adipose tissue, the large adipose tissue mass of obese patients may become insulin resistant generating large quantities of atherogenic and diabetogenic FFA.

A “two hit” model originally developed by Day and James [44] postulates that liver fat deposition because of lipid spillover from adipose tissue is only the first of two steps leading to non-alcoholic fatty liver disease. The second “hit” of the model involves either lipid peroxidation through oxidative stress and/or cytokine action [45]. The model suggests that reactive oxygen species (of yet unknown origin) can degenerate the excess lipids stored in the liver, causing both hepatic inflammation and hepatocyte damage and, eventually, death [45]. The disease may then progress from steatosis to steatohepatitis and possibly cirrhosis. It is also possible that excess liver fat storage can increase the hepatic production of bioactive molecules such as tumour necrosis factor (TNF-α), which are also capable of having a similar harmful impact on the liver [45].

A deficiency in adiponectin, another cytokine, may also play a role in the pathogenesis of liver fat [46]. Low levels of plasma adiponectin have been linked to obesity, visceral adiposity in particular [47], insulin resistance [48], and fatty liver [49,50].

Along with suppressing the production and function of TNF-α [51], adiponectin can decrease hepatic lipogenesis and increase hepatic insulin sensitivity [52,53]. Low adiponectin levels may therefore lead to liver inflammation, liver fat accumulation by reducing insulin sensitivity, and damage through TNF-α suppression. In this respect, administering adiponectin to rodents with fatty liver has been shown to resolve the condition [54].

Another possible reason for the accumulation of liver fat is high dietary consumption of saturated fats and/or carbohydrates. It has been shown that 50% of dietary fat is taken up by the liver [55], so it is not surprising that dietary fat content is related to degree of liver fat storage [56,57]. High carbohydrate intake has also been shown to play a role in liver fat content, and the restriction of dietary carbohydrate intake may reduce liver fat storage [58].

Recent evidence suggests that the endocannabinoid system, including the cannabinoid receptor CB1 and endogenous agonists such as anandamide and 2-arachidonylglycerol (2-AG), may play a role in the pathogenesis of liver fat [59,60]. It has been proposed that obesity may be associated with overactivation of the endocannabinoid system, with elevated endocannabinoids working via the hepatic CB1 receptor to stimulate hepatic lipogenesis and subsequently lead to the development of fatty liver [59,60]. More research is needed to define the role of the endocannabinoid system in the pathogenesis of fatty liver.

Measuring Liver Fat

Liver biopsy is generally considered the gold standard for assessing hepatic steatosis [17]. However, a liver biopsy sample is a mere 1/50,000 of total organ mass [61], and because liver tissue is so heterogeneous, this small sample is likely to be a biased estimate of overall hepatic steatosis. Studies using multiple biopsy samples have shown considerable sampling variability for various hepatic histological features, including the diagnosis and staging of non-alcoholic fatty liver disease [62]. A biopsy procedure can also cause post-procedure pain, hypotension, intraperitoneal hemorrhage, bacterial infection, and a small but definite risk of mortality [63].

Advanced imaging techniques such as computed tomography (CT) and proton-magnetic resonance spectroscopy (H1-MRS) have emerged as safe, reliable, and non-invasive alternatives to liver biopsy. Liver attenuation on a CT image depends on liver density, which depends on the degree of fat infiltration: the higher the fat content, the lower the attenuation value, and the darker the CT image of the liver (Figure 2). Strong correlations have been observed between CT and histological measures of liver fat (r=-0.77) [64]. H1–MRS, an alternate imaging technique that does not use x-ray energy, also correlates well with biopsy assessments of liver fat [64-66]. Though H1–MRS produces a quantitative measure of liver fat and CT a qualitative analysis [67], these measures correlate well with each other (r>0.80) [64,65]. Unfortunately, these imaging techniques only detect liver fat when over 30% of the liver tissue is already infiltrated with fat [68]. In addition, no imaging technique is capable of differentiating between degrees of non-alcoholic liver disease, particularly between hepatic steatosis and steatohepatitis [68], a clinically relevant distinction.

Elevated levels of two serum liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [19], and an AST/ALT ratio of less than 1 [69] are the common clinical criteria used to distinguish non-alcoholic fatty liver disease from alcoholic fatty liver disease. Elevated levels of these enzymes have also been tied to cardiometabolic risk factors such as abdominal obesity, elevated blood pressure, insulin resistance, and dyslipidemia [70,71] as well as risk of cardiovascular disease [72].

Liver fat deposition is associated with a number of cardiometabolic risk factors, including abdominal obesity, hypertension, insulin resistance, and dyslipidemia. A variety of methods can be used to measure liver fat, including the standard liver biopsy as well as specialized imaging techniques such as H1-MRS and CT. Many theories have been put forth to explain how fatty liver develops and how the deposition of fat in hepatic tissue increases cardiometabolic risk. The consequences of liver fat accumulation on health is an area of very active scientific research. Many studies are conducted to better understand the etiology of non-alcoholic fatty liver disease and its related cardiometabolic complications and interesting review papers have been published on the topic [73-77].

References

  1. Unger RH. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology 2003; 144: 5159-65.

    PubMed ID: 12960011
  2. Ravussin E and Smith SR. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus. Ann N Y Acad Sci 2002; 967: 363-78.

    PubMed ID: 12079864
  3. Heilbronn L, Smith SR and Ravussin E. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Int J Obes Relat Metab Disord 2004; 28 Suppl 4: S12-21.

    PubMed ID: 15592481
  4. Banerji MA, Buckley MC, Chaiken RL, et al. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM. Int. J. Obes. 1995; 19: 846-50.

    PubMed ID: 8963350
  5. Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999; 107: 450-5.

    PubMed ID: 10569299
  6. Ryysy L, Hakkinen AM, Goto T, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 2000; 49: 749-58.

    PubMed ID: 10905483
  7. Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50: 1844-50.

    PubMed ID: 11473047
  8. Tiikkainen M, Tamminen M, Hakkinen AM, et al. Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. Obes Res 2002; 10: 859-67.

    PubMed ID: 12226133
  9. Kelley DE, McKolanis TM, Hegazi RA, et al. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 2003; 285: E906-16.

    PubMed ID: 12959938
  10. Adiels M, Taskinen MR, Packard C, et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 2006; 49: 755-65.

    PubMed ID: 16463046
  11. Ueno T, Sugawara H, Sujaku K, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol 1997; 27: 103-7.

    PubMed ID: 9252081
  12. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 2002; 87: 3023-8.

    PubMed ID: 12107194
  13. Omagari K, Kadokawa Y, Masuda J, et al. Fatty liver in non-alcoholic non-overweight Japanese adults: incidence and clinical characteristics. J Gastroenterol Hepatol 2002; 17: 1098-105.

    PubMed ID: 12201871
  14. Nguyen-Duy TB, Nichaman MZ, Church TS, et al. Visceral fat and liver fat are independent predictors of metabolic risk factors in men. Am J Physiol Endocrinol Metab 2003; 284: E1065-71.

    PubMed ID: 12554597
  15. Westerbacka J, Corner A, Tiikkainen M, et al. Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk. Diabetologia 2004; 47: 1360-9.

    PubMed ID: 15309287
  16. Leevy CM. Fatty liver: a study of 270 patients with biopsy proven fatty liver and review of the literature. Medicine (Baltimore) 1962; 41: 249-76.

    PubMed ID: 14463641
  17. Angulo P and Lindor KD. Non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2002; 17 Suppl: S186-90.

    PubMed ID: 12000605
  18. Vozarova B, Stefan N, Lindsay RS, et al. High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 2002; 51: 1889-95.

    PubMed ID: 12031978
  19. Clark JM, Brancati FL and Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003; 98: 960-7.

    PubMed ID: 12809815
  20. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40: 1387-95.

    PubMed ID: 15565570
  21. Ryan CK, Johnson LA, Germin BI, et al. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl 2002; 8: 1114-22.

    PubMed ID: 12474149
  22. Tominaga K, Kurata JH, Chen YK, et al. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci 1995; 40: 2002-9.

    PubMed ID: 7555456
  23. Gupte P, Amarapurkar D, Agal S, et al. Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J Gastroenterol Hepatol 2004; 19: 854-8.

    PubMed ID: 15242486
  24. Del Gaudio A, Boschi L, Del Gaudio GA, et al. Liver damage in obese patients. Obes Surg 2002; 12: 802-4.

    PubMed ID: 12568185
  25. Ludwig J, Viggiano TR, McGill DB, et al. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55: 434-8.

    PubMed ID: 7382552
  26. Scheen AJ and Luyckx FH. Obesity and liver disease. Best Pract Res Clin Endocrinol Metab 2002; 16: 703-16.

    PubMed ID: 12468416
  27. Bellentani S, Saccoccio G, Masutti F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000; 132: 112-7.

    PubMed ID: 10644271
  28. Kim HJ, Kim HJ, Lee KE, et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med 2004; 164: 2169-75.

    PubMed ID: 15505132
  29. Jepsen P, Vilstrup H, Mellemkjaer L, et al. Prognosis of patients with a diagnosis of fatty liver–a registry-based cohort study. Hepatogastroenterology 2003; 50: 2101-4.

    PubMed ID: 14696473
  30. Marceau P, Biron S, Hould FS, et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab 1999; 84: 1513-7.

    PubMed ID: 10323371
  31. Lewis GF, Carpentier A, Adeli K, et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002; 23: 201-29.

    PubMed ID: 11943743
  32. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221-31.

    PubMed ID: 11961152
  33. Lee Y, Hirose H, Ohneda M, et al. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci U S A 1994; 91: 10878-82.

    PubMed ID: 7971976
  34. Shimabukuro M, Higa M, Zhou YT, et al. Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J Biol Chem 1998; 273: 32487-90.

    PubMed ID: 9829981
  35. Bergman RN. New concepts in extracellular signaling for insulin action: the single gateway hypothesis. Recent Prog Horm Res 1997; 52: 359-85; discussion 85-7.

    PubMed ID: 9238859
  36. Kabir M, Catalano KJ, Ananthnarayan S, et al. Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance. Am J Physiol Endocrinol Metab 2005; 288: E454-61.

    PubMed ID: 15522994
  37. Lewis GF, Uffelman KD, Szeto LW, et al. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest 1995; 95: 158-66.

    PubMed ID: 7814610
  38. Garg A. Lipodystrophies. Am J Med 2000; 108: 143-52.

    PubMed ID: 11126308
  39. Robbins DC, Horton ES, Tulp O, et al. Familial partial lipodystrophy: complications of obesity in the non-obese? Metabolism 1982; 31: 445-52.

    PubMed ID: 7043176
  40. Adams M, Montague CT, Prins JB, et al. Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. J Clin Invest 1997; 100: 3149-53.

    PubMed ID: 9399962
  41. Katoh S, Hata S, Matsushima M, et al. Troglitazone prevents the rise in visceral adiposity and improves fatty liver associated with sulfonylurea therapy–a randomized controlled trial. Metabolism 2001; 50: 414-7.

    PubMed ID: 11288035
  42. Miyazaki Y, Mahankali A, Matsuda M, et al. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care 2001; 24: 710-9.

    PubMed ID: 11315836
  43. Robinson C, Tamborlane WV, Maggs DG, et al. Effect of insulin on glycerol production in obese adolescents. Am J Physiol 1998; 274: E737-43.

    PubMed ID: 9575836
  44. Day CP and James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998; 114: 842-5.

    PubMed ID: 9547102
  45. Day CP. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 2002; 16: 663-78.

    PubMed ID: 12406438
  46. Yki-Jarvinen H. Fat in the liver and insulin resistance. Ann Med 2005; 37: 347-56.

    PubMed ID: 16179270
  47. Côté M, Mauriège P, Bergeron J, et al. Adiponectinemia in visceral obesity: impact on glucose tolerance and plasma lipoprotein and lipid levels in men. J Clin Endocrinol Metab 2005; 90: 1434-9.

    PubMed ID: 15598678
  48. Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001; 86: 1930-5.

    PubMed ID: 11344187
  49. Matsubara M. Plasma adiponectin decrease in women with nonalcoholic Fatty liver. Endocr J 2004; 51: 587-93.

    PubMed ID: 15644578
  50. Pagano C, Soardo G, Esposito W, et al. Plasma adiponectin is decreased in nonalcoholic fatty liver disease. Eur J Endocrinol 2005; 152: 113-8.

    PubMed ID: 15762194
  51. Maeda N, Shimomura I, Kishida K, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002; 8: 731-7.

    PubMed ID: 12068289
  52. Jacobi SK, Ajuwon KM, Weber TE, et al. Cloning and expression of porcine adiponectin, and its relationship to adiposity, lipogenesis and the acute phase response. J Endocrinol 2004; 182: 133-44.

    PubMed ID: 15225138
  53. Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941-6.

    PubMed ID: 11479627
  54. Xu A, Wang Y, Keshaw H, et al. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003; 112: 91-100.

    PubMed ID: 12840063
  55. Hultin M, Savonen R and Olivecrona T. Chylomicron metabolism in rats: lipolysis, recirculation of triglyceride-derived fatty acids in plasma FFA, and fate of core lipids as analyzed by compartmental modelling. J Lipid Res 1996; 37: 1022-36.

    PubMed ID: 8725154
  56. Tiikkainen M, Bergholm R, Vehkavaara S, et al. Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. Diabetes 2003; 52: 701-7.

    PubMed ID: 12606511
  57. Westerbacka J, Lammi K, Hakkinen AM, et al. Dietary fat content modifies liver fat in overweight nondiabetic subjects. J Clin Endocrinol Metab 2005; 90: 2804-9.

    PubMed ID: 15741262
  58. Okita M, Hayashi M, Sasagawa T, et al. Effect of a moderately energy-restricted diet on obese patients with fatty liver. Nutrition 2001; 17: 542-7.

    PubMed ID: 11448571
  59. Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005; 115: 1298-305.

    PubMed ID: 15864349
  60. Osei-Hyiaman D, Harvey-White J, Batkai S, et al. The role of the endocannabinoid system in the control of energy homeostasis. Int J Obes (Lond) 2006; 30 Suppl 1: S33-8.

    PubMed ID: 16570103
  61. Bravo AA, Sheth SG and Chopra S. Liver biopsy. N Engl J Med 2001; 344: 495-500.

    PubMed ID: 11172192
  62. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005; 128: 1898-906.

    PubMed ID: 15940625
  63. Thampanitchawong P and Piratvisuth T. Liver biopsy:complications and risk factors. World J Gastroenterol 1999; 5: 301-4.

    PubMed ID: 11819452
  64. Longo R, Ricci C, Masutti F, et al. Fatty infiltration of the liver. Quantification by 1H localized magnetic resonance spectroscopy and comparison with computed tomography. Invest Radiol 1993; 28: 297-302.

    PubMed ID: 8478169
  65. Longo R, Pollesello P, Ricci C, et al. Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis. J Magn Reson Imaging 1995; 5: 281-5.

    PubMed ID: 7633104
  66. Thomsen C, Becker U, Winkler K, et al. Quantification of liver fat using magnetic resonance spectroscopy. Magn Reson Imaging 1994; 12: 487-95.

    PubMed ID: 8007779
  67. Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288: E462-8.

    PubMed ID: 15339742
  68. Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 745-50.

    PubMed ID: 12198701
  69. Sorbi D, Boynton J and Lindor KD. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol 1999; 94: 1018-22.

    PubMed ID: 10201476
  70. Bruckert E, Giral P, Ratziu V, et al. A constellation of cardiovascular risk factors is associated with hepatic enzyme elevation in hyperlipidemic patients. Metabolism 2002; 51: 1071-6.

    PubMed ID: 12145784
  71. Ruhl CE and Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology 2003; 124: 71-9.

    PubMed ID: 12512031
  72. Ioannou GN, Weiss NS, Boyko EJ, et al. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology 2006; 43: 1145-51.

    PubMed ID: 16628637
  73. Stefan N, Häring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019;7:313-324.

    PubMed ID: 30174213
  74. Ruissen MM, Mak AL, Beuers U, Tushuizen ME, Holleboom AG. Non-alcoholic fatty liver disease: a multidisciplinary approach towards a cardiometabolic liver disease. Eur J Endocrinol. 2020;183:R57-R73.

    PubMed ID: 32508312
  75. Targher G, Byrne CD, Tilg H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut. 2020;69:1691-1705.

    PubMed ID: 32321858
  76. Budd J, Cusi K. Nonalcoholic fatty liver disease: What does the primary care physician need to know? Am J Med. 2020;133:536-543.

    PubMed ID: 32017891
  77. Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73:202-209.

    PubMed ID: 32278004
Reference 1 CLOSECLOSE

Unger RH. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology 2003; 144: 5159-65.

PubMed ID: 12960011
Reference 2 CLOSECLOSE

Ravussin E and Smith SR. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus. Ann N Y Acad Sci 2002; 967: 363-78.

PubMed ID: 12079864
Reference 3 CLOSECLOSE

Heilbronn L, Smith SR and Ravussin E. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Int J Obes Relat Metab Disord 2004; 28 Suppl 4: S12-21.

PubMed ID: 15592481
Reference 4 CLOSECLOSE

Banerji MA, Buckley MC, Chaiken RL, et al. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM. Int. J. Obes. 1995; 19: 846-50.

PubMed ID: 8963350
Reference 5 CLOSECLOSE

Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999; 107: 450-5.

PubMed ID: 10569299
Reference 6 CLOSECLOSE

Ryysy L, Hakkinen AM, Goto T, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 2000; 49: 749-58.

PubMed ID: 10905483
Reference 7 CLOSECLOSE

Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50: 1844-50.

PubMed ID: 11473047
Reference 8 CLOSECLOSE

Tiikkainen M, Tamminen M, Hakkinen AM, et al. Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. Obes Res 2002; 10: 859-67.

PubMed ID: 12226133
Reference 9 CLOSECLOSE

Kelley DE, McKolanis TM, Hegazi RA, et al. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 2003; 285: E906-16.

PubMed ID: 12959938
Reference 10 CLOSECLOSE

Adiels M, Taskinen MR, Packard C, et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 2006; 49: 755-65.

PubMed ID: 16463046
Reference 11 CLOSECLOSE

Ueno T, Sugawara H, Sujaku K, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol 1997; 27: 103-7.

PubMed ID: 9252081
Reference 12 CLOSECLOSE

Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 2002; 87: 3023-8.

PubMed ID: 12107194
Reference 13 CLOSECLOSE

Omagari K, Kadokawa Y, Masuda J, et al. Fatty liver in non-alcoholic non-overweight Japanese adults: incidence and clinical characteristics. J Gastroenterol Hepatol 2002; 17: 1098-105.

PubMed ID: 12201871
Reference 14 CLOSECLOSE

Nguyen-Duy TB, Nichaman MZ, Church TS, et al. Visceral fat and liver fat are independent predictors of metabolic risk factors in men. Am J Physiol Endocrinol Metab 2003; 284: E1065-71.

PubMed ID: 12554597
Reference 15 CLOSECLOSE

Westerbacka J, Corner A, Tiikkainen M, et al. Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk. Diabetologia 2004; 47: 1360-9.

PubMed ID: 15309287
Reference 16 CLOSECLOSE

Leevy CM. Fatty liver: a study of 270 patients with biopsy proven fatty liver and review of the literature. Medicine (Baltimore) 1962; 41: 249-76.

PubMed ID: 14463641
Reference 17 CLOSECLOSE

Angulo P and Lindor KD. Non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2002; 17 Suppl: S186-90.

PubMed ID: 12000605
Reference 18 CLOSECLOSE

Vozarova B, Stefan N, Lindsay RS, et al. High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 2002; 51: 1889-95.

PubMed ID: 12031978
Reference 19 CLOSECLOSE

Clark JM, Brancati FL and Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003; 98: 960-7.

PubMed ID: 12809815
Reference 20 CLOSECLOSE

Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40: 1387-95.

PubMed ID: 15565570
Reference 21 CLOSECLOSE

Ryan CK, Johnson LA, Germin BI, et al. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl 2002; 8: 1114-22.

PubMed ID: 12474149
Reference 22 CLOSECLOSE

Tominaga K, Kurata JH, Chen YK, et al. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci 1995; 40: 2002-9.

PubMed ID: 7555456
Reference 23 CLOSECLOSE

Gupte P, Amarapurkar D, Agal S, et al. Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J Gastroenterol Hepatol 2004; 19: 854-8.

PubMed ID: 15242486
Reference 24 CLOSECLOSE

Del Gaudio A, Boschi L, Del Gaudio GA, et al. Liver damage in obese patients. Obes Surg 2002; 12: 802-4.

PubMed ID: 12568185
Reference 25 CLOSECLOSE

Ludwig J, Viggiano TR, McGill DB, et al. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55: 434-8.

PubMed ID: 7382552
Reference 26 CLOSECLOSE

Scheen AJ and Luyckx FH. Obesity and liver disease. Best Pract Res Clin Endocrinol Metab 2002; 16: 703-16.

PubMed ID: 12468416
Reference 27 CLOSECLOSE

Bellentani S, Saccoccio G, Masutti F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000; 132: 112-7.

PubMed ID: 10644271
Reference 28 CLOSECLOSE

Kim HJ, Kim HJ, Lee KE, et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med 2004; 164: 2169-75.

PubMed ID: 15505132
Reference 29 CLOSECLOSE

Jepsen P, Vilstrup H, Mellemkjaer L, et al. Prognosis of patients with a diagnosis of fatty liver–a registry-based cohort study. Hepatogastroenterology 2003; 50: 2101-4.

PubMed ID: 14696473
Reference 30 CLOSECLOSE

Marceau P, Biron S, Hould FS, et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab 1999; 84: 1513-7.

PubMed ID: 10323371
Reference 31 CLOSECLOSE

Lewis GF, Carpentier A, Adeli K, et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002; 23: 201-29.

PubMed ID: 11943743
Reference 32 CLOSECLOSE

Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221-31.

PubMed ID: 11961152
Reference 33 CLOSECLOSE

Lee Y, Hirose H, Ohneda M, et al. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci U S A 1994; 91: 10878-82.

PubMed ID: 7971976
Reference 34 CLOSECLOSE

Shimabukuro M, Higa M, Zhou YT, et al. Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J Biol Chem 1998; 273: 32487-90.

PubMed ID: 9829981
Reference 35 CLOSECLOSE

Bergman RN. New concepts in extracellular signaling for insulin action: the single gateway hypothesis. Recent Prog Horm Res 1997; 52: 359-85; discussion 85-7.

PubMed ID: 9238859
Reference 36 CLOSECLOSE

Kabir M, Catalano KJ, Ananthnarayan S, et al. Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance. Am J Physiol Endocrinol Metab 2005; 288: E454-61.

PubMed ID: 15522994
Reference 37 CLOSECLOSE

Lewis GF, Uffelman KD, Szeto LW, et al. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest 1995; 95: 158-66.

PubMed ID: 7814610
Reference 38 CLOSECLOSE

Garg A. Lipodystrophies. Am J Med 2000; 108: 143-52.

PubMed ID: 11126308
Reference 39 CLOSECLOSE

Robbins DC, Horton ES, Tulp O, et al. Familial partial lipodystrophy: complications of obesity in the non-obese? Metabolism 1982; 31: 445-52.

PubMed ID: 7043176
Reference 40 CLOSECLOSE

Adams M, Montague CT, Prins JB, et al. Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. J Clin Invest 1997; 100: 3149-53.

PubMed ID: 9399962
Reference 41 CLOSECLOSE

Katoh S, Hata S, Matsushima M, et al. Troglitazone prevents the rise in visceral adiposity and improves fatty liver associated with sulfonylurea therapy–a randomized controlled trial. Metabolism 2001; 50: 414-7.

PubMed ID: 11288035
Reference 42 CLOSECLOSE

Miyazaki Y, Mahankali A, Matsuda M, et al. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care 2001; 24: 710-9.

PubMed ID: 11315836
Reference 43 CLOSECLOSE

Robinson C, Tamborlane WV, Maggs DG, et al. Effect of insulin on glycerol production in obese adolescents. Am J Physiol 1998; 274: E737-43.

PubMed ID: 9575836
Reference 44 CLOSECLOSE

Day CP and James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998; 114: 842-5.

PubMed ID: 9547102
Reference 45 CLOSECLOSE

Day CP. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 2002; 16: 663-78.

PubMed ID: 12406438
Reference 46 CLOSECLOSE

Yki-Jarvinen H. Fat in the liver and insulin resistance. Ann Med 2005; 37: 347-56.

PubMed ID: 16179270
Reference 47 CLOSECLOSE

Côté M, Mauriège P, Bergeron J, et al. Adiponectinemia in visceral obesity: impact on glucose tolerance and plasma lipoprotein and lipid levels in men. J Clin Endocrinol Metab 2005; 90: 1434-9.

PubMed ID: 15598678
Reference 48 CLOSECLOSE

Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001; 86: 1930-5.

PubMed ID: 11344187
Reference 49 CLOSECLOSE

Matsubara M. Plasma adiponectin decrease in women with nonalcoholic Fatty liver. Endocr J 2004; 51: 587-93.

PubMed ID: 15644578
Reference 50 CLOSECLOSE

Pagano C, Soardo G, Esposito W, et al. Plasma adiponectin is decreased in nonalcoholic fatty liver disease. Eur J Endocrinol 2005; 152: 113-8.

PubMed ID: 15762194
Reference 51 CLOSECLOSE

Maeda N, Shimomura I, Kishida K, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002; 8: 731-7.

PubMed ID: 12068289
Reference 52 CLOSECLOSE

Jacobi SK, Ajuwon KM, Weber TE, et al. Cloning and expression of porcine adiponectin, and its relationship to adiposity, lipogenesis and the acute phase response. J Endocrinol 2004; 182: 133-44.

PubMed ID: 15225138
Reference 53 CLOSECLOSE

Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941-6.

PubMed ID: 11479627
Reference 54 CLOSECLOSE

Xu A, Wang Y, Keshaw H, et al. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003; 112: 91-100.

PubMed ID: 12840063
Reference 55 CLOSECLOSE

Hultin M, Savonen R and Olivecrona T. Chylomicron metabolism in rats: lipolysis, recirculation of triglyceride-derived fatty acids in plasma FFA, and fate of core lipids as analyzed by compartmental modelling. J Lipid Res 1996; 37: 1022-36.

PubMed ID: 8725154
Reference 56 CLOSECLOSE

Tiikkainen M, Bergholm R, Vehkavaara S, et al. Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. Diabetes 2003; 52: 701-7.

PubMed ID: 12606511
Reference 57 CLOSECLOSE

Westerbacka J, Lammi K, Hakkinen AM, et al. Dietary fat content modifies liver fat in overweight nondiabetic subjects. J Clin Endocrinol Metab 2005; 90: 2804-9.

PubMed ID: 15741262
Reference 58 CLOSECLOSE

Okita M, Hayashi M, Sasagawa T, et al. Effect of a moderately energy-restricted diet on obese patients with fatty liver. Nutrition 2001; 17: 542-7.

PubMed ID: 11448571
Reference 59 CLOSECLOSE

Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005; 115: 1298-305.

PubMed ID: 15864349
Reference 60 CLOSECLOSE

Osei-Hyiaman D, Harvey-White J, Batkai S, et al. The role of the endocannabinoid system in the control of energy homeostasis. Int J Obes (Lond) 2006; 30 Suppl 1: S33-8.

PubMed ID: 16570103
Reference 61 CLOSECLOSE

Bravo AA, Sheth SG and Chopra S. Liver biopsy. N Engl J Med 2001; 344: 495-500.

PubMed ID: 11172192
Reference 62 CLOSECLOSE

Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005; 128: 1898-906.

PubMed ID: 15940625
Reference 63 CLOSECLOSE

Thampanitchawong P and Piratvisuth T. Liver biopsy:complications and risk factors. World J Gastroenterol 1999; 5: 301-4.

PubMed ID: 11819452
Reference 64 CLOSECLOSE

Longo R, Ricci C, Masutti F, et al. Fatty infiltration of the liver. Quantification by 1H localized magnetic resonance spectroscopy and comparison with computed tomography. Invest Radiol 1993; 28: 297-302.

PubMed ID: 8478169
Reference 65 CLOSECLOSE

Longo R, Pollesello P, Ricci C, et al. Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis. J Magn Reson Imaging 1995; 5: 281-5.

PubMed ID: 7633104
Reference 66 CLOSECLOSE

Thomsen C, Becker U, Winkler K, et al. Quantification of liver fat using magnetic resonance spectroscopy. Magn Reson Imaging 1994; 12: 487-95.

PubMed ID: 8007779
Reference 67 CLOSECLOSE

Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288: E462-8.

PubMed ID: 15339742
Reference 68 CLOSECLOSE

Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 745-50.

PubMed ID: 12198701
Reference 69 CLOSECLOSE

Sorbi D, Boynton J and Lindor KD. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol 1999; 94: 1018-22.

PubMed ID: 10201476
Reference 70 CLOSECLOSE

Bruckert E, Giral P, Ratziu V, et al. A constellation of cardiovascular risk factors is associated with hepatic enzyme elevation in hyperlipidemic patients. Metabolism 2002; 51: 1071-6.

PubMed ID: 12145784
Reference 71 CLOSECLOSE

Ruhl CE and Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology 2003; 124: 71-9.

PubMed ID: 12512031
Reference 72 CLOSECLOSE

Ioannou GN, Weiss NS, Boyko EJ, et al. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology 2006; 43: 1145-51.

PubMed ID: 16628637
Reference 73 CLOSECLOSE

Stefan N, Häring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019;7:313-324.

PubMed ID: 30174213
Reference 74 CLOSECLOSE

Ruissen MM, Mak AL, Beuers U, Tushuizen ME, Holleboom AG. Non-alcoholic fatty liver disease: a multidisciplinary approach towards a cardiometabolic liver disease. Eur J Endocrinol. 2020;183:R57-R73.

PubMed ID: 32508312
Reference 75 CLOSECLOSE

Targher G, Byrne CD, Tilg H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut. 2020;69:1691-1705.

PubMed ID: 32321858
Reference 76 CLOSECLOSE

Budd J, Cusi K. Nonalcoholic fatty liver disease: What does the primary care physician need to know? Am J Med. 2020;133:536-543.

PubMed ID: 32017891
Reference 77 CLOSECLOSE

Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73:202-209.

PubMed ID: 32278004