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ISRN Gastroenterol. 2011; 2011: 592404.
Published online 2011 August 28. doi:  10.5402/2011/592404
PMCID: PMC3168494
Copyright © 2011 M. S. Mirza.
Obesity, Visceral Fat, and NAFLD: Querying the Role of Adipokines in the Progression of Nonalcoholic Fatty Liver Disease
M. S. Mirza *
SpR Surgery, Ninewells Hospital, 65 Lister Court, Dundee DD2 1UY, UK
*M. S. Mirza: msmirza/at/doctors.org.uk
Academic Editors: K. D. Mullen, C. T. Shun, and W. Vogel
Received April 4, 2011; Accepted May 1, 2011.
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of clinicopathologic conditions ranging from steatosis alone to nonalcoholic steatohepatitis (NASH), with varying risks for progression to cirrhosis and hepatocellular carcinoma. There is mounting evidence that NAFLD not only complicates obesity, but also perpetuates its metabolic consequences. Critical event that leads to progressive liver injury in NAFLD is unknown. Obesity reflects a generalized proinflammatory state with its increased inflammatory markers like C reactive protein, IL-6, IL-8, IL-10, PAI-1, TNF-α, and hepatocyte growth factor. The elevated production of these adipokines is increasingly considered to be important in the development of diseases linked to obesity and the metabolic syndrome. Disordered cytokine production is likely to play a role in the pathogenesis of NAFLD. There is no effective treatment for NAFLD, though weight loss may halt disease progression and revert histological changes, the underlying mechanism remaining elusive. All stages of the disease pathway from prevention, early identification/diagnosis, and treatment require an understanding of the pathogenesis of liver injury in NAFLD.
With the rapidly growing prevalence of obesity [1] throughout the world, morbidity and mortality related to its complications is on the rise [2]. Obesity is considered a gateway disease. Defined and classified by body mass index (Table 1), individuals with severe obesity have a disproportionately high risk of comorbidities including nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and diabetes [3–6]. NAFLD now represents the most common of all liver disorders and the most frequent cause of chronic liver disease [7]. It is a syndrome with multifactorial aetiology with which obesity is most commonly associated [8]. Obesity itself is typically a heterogeneous condition due to the regional distribution of fat tissue. There is growing evidence that the distribution of adipose tissue in the body is of importance for the development of the metabolic complications of obesity. Adipose tissue as an endocrine organ has become accepted [9, 10] with the distinctive biological properties of visceral adipose tissue presumably contributing to the increased pathogenecity of obesity.
Table 1
Table 1
WHO classification of overweight and obesity [2].
Metabolic syndrome or syndrome X (Tables ​(Tables2(a),2(a), ​(a),2(b)2(b) and ​and3),3), is a constellation of closely related cardiovascular risk factors characterized by obesity, insulin resistance, hyperinsulinemia, hyperglycaemia, dyslipidemia, and hypertension [11–15]. Its pathological basis still remains elusive. Often associated with insensitivity to insulin, obesity is considered a key factor in the development of the metabolic syndrome. In obese individuals, fatty tissue becomes insensitive to the action of insulin resulting in greater breakdown of triglycerides [16]. Overabundance of circulating free fatty acids from excessive adiposity contributes to the development of insulin resistance [16]. Upon reaching insulin sensitive tissues, excessive fatty acids create insulin resistance by the added substrate availability and by modifying downstream signaling [16]. The release of adipose tissue-derived proteohormones called adipokines also comes under the influence of insulin. Under normal weight conditions, adipokines guarantee homeostasis of glucose and lipid metabolism. Their dysregulated production in the obese state is associated with insulin resistance and appears to play an important role in the development of the metabolic syndrome [16, 17]. Resistance to Leptin, an important adipokine has been suggested as an alternative concept to explain the metabolic syndrome [16, 18]. In general, conditions like obesity in which leptin deficiency or resistance are present are associated with triglyceride accumulation in nonadipose organs like liver, muscle, and pancreas [16, 18]. The resulting lipotoxicity in these organs results in diabetes by causing insulin resistance. Leptin also seems to lower insulin secretion [16, 19]. Leptin resistance, however, could relate to the hyperinsulinemia of the metabolic syndrome [16, 20].
Table 2
Table 2
(a) International Diabetes Foundation; metabolic syndrome worldwide definition [15, 24]. (b) Country-/ethnicity-specific values for waist circumference [15, 24].
Table 3
Table 3
The Third US National Health and Nutrition Examination Survey (NHANES III) clinical criteria for the presence of metabolic syndrome (presence of ≥3 criteria) [25].
NAFLD represents the hepatic component of the metabolic syndrome [14, 41]. Insulin resistance is a universal phenomenon in NAFLD [14, 42, 43]. The presence of metabolic syndrome carries a high risk of necroinflammation and fibrosis among NAFLD subjects and remains strongly correlated with disease severity and progression [13, 14]. Specific adipokines may link the metabolic syndrome, type 2 diabetes and NAFLD and an imbalance in adipokine expression could play a pivotal role in disease progression to NASH and cirrhosis.
Fat is not uniformly distributed in the body (Table 4). Visceral fat depots are located in the body cavity beneath the abdominal muscles and composed of greater and lesser omentum and the mesenteric fat [23, 25, 44]. A lesser amount of visceral fat is located retroperitoneally [23, 25, 44]. In general, visceral fat accounts for up to 20% of total fat in men and 5–8% in women [44]. The abdominal subcutaneous fat is located immediately beneath the skin and on top of the abdominal musculature [25, 44]. The predominance of lower body fat is subcutaneous most of which is stored in the femoral and gluteal regions [23, 44] (Table 2).
Table 4
Table 4
Body fat distribution [27].
The distribution of fat appears more important than the total fat mass in obesity [23, 45] (Table 2). A predominantly upper body fat distribution increases the risks for the metabolic complications of obesity including hepatic steatosis especially when it is associated with increased intra-abdominal fat [46–49]. Most “metabolically obese” normal weight subjects have some increase in adipose tissue mass and insulin resistance probably due to an increase in visceral fat [25]. Thus, subjects with a relatively low BMI can have gross increases in abdominal visceral fat [25, 50, 51], and others with a high BMI may have very little intra abdominal/visceral fat [25, 52].
Adipose tissue comprises of mature adipocytes, preadipocytes, stromovascular cells, connective tissue matrix, endothelial cells, sympathetic nerve fibres, and macrophages which may all contribute to adipose tissue function [26, 49, 53] In addition, it expresses numerous receptors that allow it to respond to afferent signals from traditional hormone systems as well as the central nervous system [49]. The cellular composition of fat can vary substantially according to anatomical location and body weight. The anatomic location of each adipose tissue depot itself affects endocrine function [25, 26, 49]. Fat mass can increase in one of two ways: individual adipocytes can increase in volume, or they can increase in number as more are derived from preadipocytes [44]. Fat cell size is an important determinant of the metabolic activity of the fat depot [45]. Visceral adipocytes are somewhat smaller than subcutaneous cells [54–56], though omental fat cell size does not differ significantly from subcutaneous adipocyte [56]. Enlarged fat cells appear to secrete increased amounts of adipokines [55, 57, 58].
The stromal vascular fraction of adipose tissue contributes to the major differences between subcutaneous and visceral fat including adipokine production. The number of stromal vascular cells per gram of adipose tissue are reported to be higher in omental compared to subcutaneous fat possibly to be due to higher number of endothelial cells in the omental fat [59]. On the other hand stromal cells from subcutaneous fat proliferate faster than those from the omental region [59]. Another component of adipose tissue, the preadipocytes, has been shown by some to show greater differentiation capacity in case of subcutaneous fat compared to visceral adipose tissue but not by others [44, 59, 60].
The increased fat mass assumes greater significance with recent recognition of the adipocyte as an endocrine organ capable of secreting a variety of bioactive peptides that exert multiple effects at both the local and systemic level [7, 49]. To date, over fifty “adipokines” have been reported to be secreted by adipose tissue that not only influence body weight homeostasis but also inflammation, coagulation, fibrinolysis, insulin resistance, diabetes, atherosclerosis, and some forms of cancer [53, 61]. These include leptin, adiponectin, resistin, acylation stimulating protein, TNF-α, TGF-β, plasminogen activator inhibitor, angiotensin II, and interleukins 6, 8, 10 [49, 53] to name a few.
The vascular anatomy and metabolic activity of fat from various depots differ in a way that may explain the association of visceral but not subcutaneous fat with obesity-related cardiovascular and metabolic problems [23, 25, 46, 58, 62] (Tables ​(Tables55 and ​and6).6). Regional differences are pronounced between omental and subcutaneous fat depots [26–29, 53]. The venous drainage of visceral fat is via the portal system, directly providing free fatty acids as a substrate for hepatic lipoprotein metabolism and glucose production [23, 30, 45, 48]. Visceral omental fat has a higher rate of lipid turn over than subcutaneous fat [30, 63, 64] and omental adipocytes have higher basal and adrenaline-stimulated levels of intracellular cAMP [30, 65] being more responsive to the lipolytic effects of catecholamines [31, 64, 66], and less responsive to the antilipolytic effects of insulin [30, 64, 67, 68]. Omental adipocytes express higher levels of glucocorticoid receptors [25, 30, 69], and in very obese individuals express lower levels of lipoprotein lipase protein and mRNA than do subcutaneous adipocytes [30, 70]. Expression of IL-6, IL-8, resistin, PAI-1, MCP-1, and Visfatin is relatively greater in visceral fat compared to subcutaneous fat, whereas leptin, adiponectin, and adipsin are greater in subcutaneous adipose tissue [26, 30–36, 49, 57, 71]. There is no important regional variation of TNF-α production [25, 31, 71].
Table 5
Table 5
Regional differences in lipolysis [27, 48].
Table 6
Table 6
Differences in adipocytokines expression between visceral and subcutaneous fat in humans [28, 38, 49–52, 57, 63–67, 75].
Taken as a whole, these observations suggest that visceral adipocytes may represent a specialised adipocyte population designed to release nutrients rapidly in conditions of stress.
Obesity has been characterized by a state of chronic low- grade inflammation [72, 73]. The basis of this view is an increased circulating level of several inflammatory markers in the obese including CRP, TNF-α, IL-6, IL-8, IL-18, MIF, haptoglobin, SAA, and PAI-1 [72, 74–76]. The inflammatory state may be causal in the development of insulin resistance and the metabolic syndrome [72, 76]. It remains unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors and whether there is a generalised or local state of inflammation [72]. The increased production of adipokines and acute-phase proteins in obesity is considered to be primarily related to local events within the expanding fat depots [72]. With increasing evidence of the infiltration of adipose tissue by macrophages the nonadipocyte fraction may be a significant component of the inflammatory state within the fat tissue [77, 78]. Why the secretion of adipokines and other inflammation-related proteins from adipose tissue rises sharply with increasing adiposity remains obscure. It has been proposed that relative hypoxia of clusters of adipocytes within an expanding adipose tissue mass triggers the inflammatory response [72].
Nonalcoholic fatty liver disease is a form of chronic liver disease histologically indistinguishable from alcoholic hepatitis occurring in individuals without significant alcohol consumption [79, 80]. NAFLD comprises a morphologic spectrum of liver lesions (Table 1) ranging from steatosis alone to nonalcoholic steatohepatitis (NASH), with varying risks for progression to cirrhosis [38, 79, 81]. Whereas nonalcoholic steatosis without necroinflammatory change is generally a benign condition, NASH defines the turning point in the progression of NAFLD from steatosis to advanced fibrosis and cirrhosis [8]. NASH is characterized by hepatocellular steatosis, necroinflammation, hepatocellular injury, and pericellular or perisinusoidal fibrosis [7, 82]. Isolated portal inflammation/fibrosis (IPF) signifies a subset of individuals with NAFLD who have portal fibrosis associated with hepatic steatosis in the absence of zone 3 hepatocellular injuries [83–89]. It is thought to mark the onset of disease progression [90].
5. Histological Criteria for Diagnosis
The principal histologic feature of NAFLD is the presence of macrovesicular fatty change in hepatocytes with displacement of the nucleus to the edge of the cell wall [38, 39, 91]. Additional features present variably are Mallory bodies, ballooning degeneration, predominantly lobular neutrophilic inflammation, and zone III perisinusoidal fibrosis [38, 39, 91]. In many cases, atypical features like predominantly lymphocytic inflammation and/or portal fibrosis may be seen [38, 39, 91].
In the 1970s, fatty liver hepatitis was noticed to affect morbidly obese patients who had undergone jejunoileal bypass [92]. This was recognised as a new disease entity by Ludwig who in 1980 coined the term nonalcoholicsteatohepatitis (NASH) for it. [93]. Later histopathological changes consistent with the different grades of NAFLD were reported with certain drugs including steroids, amiodarone, and isoniazid [94–96] (Table 7). Increasingly, this entity has been expanded by its recognition as an important differential in the diagnosis of abnormal liver enzymes [97]. The prevalence of NAFLD/NASH appears to parallel the degree of obesity [7, 79, 80, 82, 98].The prevalence of simple steatosis in obese patients is 70–100%, whereas NASH is found in 20–25% and 2-3% have cirrhosis [88, 89, 99–101]. The prevalence of IPF is approximately 29% [12, 14, 24, 27–29, 62]. Many patients with cryptogenic cirrhosis have metabolic risk factors for NAFLD and are likely to represent cases of previously unrecognised NAFLD [102, 103]. In cirrhosis, both steatosis and inflammatory changes may have disappeared making the cause difficult to establish [11, 38, 39].
Table 7
Table 7
Grading and Staging of NAFLD [79, 90, 92].
The liver plays a central role in lipid metabolism, importing serum-free fatty acids (FFA) and manufacturing, storing, and exporting lipids and lipoproteins. However, the patho-physiology that leads to NAFLD is not well understood; in particular, the factors that lead to progressive hepatocellular damage after triglyceride accumulation are not well elucidated. The two metabolic abnormalities most strongly associated with NAFLD are insulin resistance and an increased supply of fatty acids to the liver [104].
The “two- hit” hypothesis remains the leading theory of the pathogenesis of NAFLD [105, 106]. The “first hit,” insulin resistance, leads to steatosis as a consequence to the alterations in lipid metabolism [105, 106]. Insulin resistance results in increased FFA release from the fat stores. Hepatic FFA activity is largely uncontrolled and therefore directly proportional to plasma FFA concentrations. In the liver, FFA can either be oxidised to generate ATP or esterified to produce triglycerides which can be stored or incorporated into very low density lipoproteins for export. Defects in either of these two pathways could lead to hepatic steatosis. Hepatic lipid accumulation does not universally result in liver injury indicating that additional secondary insults are important [105]. Progression to inflammation and fibrosis appears from oxidative stress, the “second hit,” triggered by the accumulation of fatty acids producing more oxidant substances than the antioxidant processes of the liver can handle [105, 106]. Lipid peroxidation and liver damage may be influenced by a variety of factors such as cytochrome P450 2E1 induction, endotoxin, hepatic iron, Kupffer cell dysfunction, and mitochondria changes and ATP homeostasis [38, 105]. Insulin resistance can contribute to all these pathways. Portal inflammation appears to mark the occurrence of this “second hit” [90]. Alterations in the adipokines resistin, leptin, adiponectin, and TNF-α are thought also to play a role in the pathogenesis [11, 38] of NAFLD.
Most patients with NAFLD are asymptomatic, and typically patients are found incidentally to have abnormal biochemical liver function tests or hepatomegaly when evaluated for another condition [107, 108]. A percentage of patients present with ill-defined symptoms of right upper quadrant pain, abdominal discomfort, fatigue, or malaise [40, 97, 109, 110]. Laboratory tests are nonspecific. Most patients have a moderate elevation in transaminases, and the ALT/AST ratio is usually less than one [108]. A variable elevation of alkaline phosphatase and gammaglutamyl transpeptidase is frequent [108]. Unexplained persistent elevation of ALT is most commonly due to NAFLD once hepatitis C and other chronic liver diseases have been excluded, [91, 111]. Up to 50% have diabetes or glucose intolerance and up to 80% may reveal fasting hypertriglyceridemia [93, 109, 112, 113]. An increase of iron in the liver accompanied by an elevated saturation of transferrin and serum ferritin may be present [109]. Antinuclear antibodies have been noted in 10%–25% of NAFLD patients, the significance of which remains unclear [93, 114, 115].
Imaging studies including ultrasonography, CT scanning, and MRI are useful in demonstrating hepatic steatosis, at least when fat accumulation is moderate to severe [116–119]. However, these tests may underestimate less severe steatosis and cannot detect the differences between NASH and nonprogressive NAFLD [118–122] Liver biopsy remains the gold standard in the diagnosis and staging of NAFLD [7, 82]. It is the only diagnostic test that reliably identifies and quantifies hepatic steatosis, inflammation, necrosis, and fibrosis; and thereby estimates prognosis and disease progression [8, 120, 123–125]. It is recommended during bariatric surgery to assess the extent of liver damage, the behaviour of liver architecture after weight loss, and the relevance of NASH in the evolution to cirrhosis [126, 127]. In addition to confirming the clinical diagnosis, liver biopsy is valuable for excluding other liver disease and for monitoring treatment efficacy [82, 128, 129]. Disadvantages to biopsy include observer variability, sampling variation, and morbidity and mortality [130].
To date, few investigations have specifically addressed sampling error and variability in NASH. Sampling variability has the potential to significantly alter disease grade and stage. The histological findings of NAFLD are usually presumed to be homogenously distributed throughout the liver. Consequently, in clinical practice, a single random core biopsy is usually considered representative of overall hepatic involvement. However, there are no data to support these assumptions in NASH [131].
Broadly, two different types of liver biopsy techniques are in use: core (needle) biopsy and wedge biopsy. Needle biopsy can be obtained percutaneously either blindly or under radiological or ultrasound guidance and by transjugular catheter [130, 132, 133]. Both types of biopsies can be taken during laparoscopic or open surgery [130, 132–134]. Core biopsy has declined considerably at laparotomy or laparoscopy and is now used mainly when focal lesions are discovered during routine surgery [133]. Wedge biopsy of the liver yields more accurate diagnosis of liver diseases than does needle biopsy, but is more invasive and haemostasis more problematic [135].
Types of biopsy needles include: the Tru-Cut, which is a cutting needle, and the Menghini needle, which uses a suction technique [132, 133, 136]. The cutting needle usually produces a larger sample, but is associated with a higher risk of complications. A suction needle tends to produce more fragmented samples [132, 137]. The size of the specimen varies depending on the size of needle: a biopsy obtained with 14-gauge(G) to 21G needle is usually defined as large, whereas needles less than 21G result in thin or fine biopsy samples with a core less than 1 mm in diameter. The size of the biopsy specimen that varies between 1 and 3 cm in length and between 1.2 and 2 mm in diameter represents 1/50,000 to 1/100,000th of the total mass of the liver [130, 132, 133]. The traditional assumption that a sample 1.5 cm long or containing four to six portal tracts, or both, is adequate is no longer true for the grading and staging of chronic liver disease. Studies show that smaller samples significantly underestimate the disease severity and samples at least 2 cm long can ensure greater diagnostic accuracy [133, 138].
In NAFLD, the distinction between steatosis and steatohepatitis and the assessment of the severity rely entirely on liver histology. Small unrepresentative samples in the context of uneven distribution of lesions can result in substantial misdiagnosis and staging inaccuracies. In addition, important pathology can be overlooked if only a single biopsy specimen is taken. It is suggested that three consecutive specimens may improve the diagnostic yield of liver biopsy [139]. While sampling error has been studied fairly extensively in cases of needle biopsy, this is not true in cases of wedge liver biopsy especially in the context of NASH.
Knowledge about the natural history of NAFLD is still evolving. There are several distinct histologic states that indicate progression of the lesion: fatty liver alone, steatohepatitis, steatohepatitis with fibrosis, and eventually cirrhosis [91, 97]. The precise risk of mortality in patients with NAFLD is not known. Preliminary studies suggest a more benign course for simple steatosis and the mortality remains low, although some have shown occasional progression to cirrhosis [38, 40, 140]. Cross-sectional series have shown that 30–40% of patients with NASH have advanced liver fibrosis at the time of presentation [91, 97, 141], whereas 10–15% may have established cirrhosis [7, 109, 141]. The risk for developing increased fibrosis in NASH over 5 years is 25% and for developing cirrhosis is 15% [38, 97, 142]. The 5- and-10 year survival in NASH has been estimated at 67% and 59% respectively, although death may arise from comorbid conditions [38, 143]. NAFLD is a leading cause of “cryptogenic cirrhosis” in which aetiologically specific clinical, laboratory, or pathological features can no longer be identified [102, 144, 145]. NAFLD-associated cirrhosis can develop into subacute liver failure, progress to hepatocellular carcinoma, and recur posttransplantation [125, 144, 146]. Thus, it appears that NAFLD is associated with the entire spectrum of chronic liver disease: progressive fibrosis, cirrhosis, end-stage liver disease, and hepatocellular carcinoma. A number of risk factors have been identified as predictors for progressive fibrosis and cirrhosis in NAFLD including; BMI > 30, type II diabetes, age > 45 years, and an ALT : AST ratio > 1 [7].
Histologic improvement may also occur with weight loss, especially in those with only minimal fibrosis [147]. This is particularly true when weight loss is achieved slowly [147, 148]. Rapid weight loss has been noted to accelerate disease progression [101, 149, 150]. Liver failure becomes manifest in many cases during a period of rapid weight loss regardless of its mechanism [101, 149, 151].
It is clear that patients with NAFLD and even more so with NASH have a serious liver disease with a fibrogenic potential that can result in liver-related morbidity and mortality.
Despite the high prevalence of NAFLD and its potential for serious sequelae, the underlying aetiological factors that determine disease progression from simple steatosis to NASH and cirrhosis remain poorly understood. Disordered adipokine production is likely to play a role in the pathogenesis of NAFLD [106, 152]. Adipokines are implicated in the pathogenesis of NAFLD/NASH through their metabolic and pro-/anti-inflammatory activity [153]. The literature reveals quantitative and qualitative differences in the repertoires of mediators that are released from peripheral and visceral fat depots [154, 155] (Table 6). The net adipokine profile generated by visceral fat appears more noxious than that of subcutaneous fat [60]. Hence, visceral adiposity accompanies the metabolic syndrome [60, 154]. Increasing visceral obesity is thought to result in increased production of proinflammatory cytokines and adipokines [tumour necrosis factor alpha, interleukin 6, and C reactive protein] [26, 156–158] and decreased production of protective adipokines [adiponectin] [28, 153, 156]. This abnormal balance might ultimately lead to the clinical and histopathological occurrence of NASH.
The exact role of adipokines in the pathogenesis of NAFLD, however, remains investigative. Literature reveals variable results about alteration in leptin [159–161], adiponectin, and TNF-α [153, 162] while the role of resistin in NAFLD in humans still awaits to be examined [162–164] though increased resistin levels have been correlated with NAFLD severity and NASH development [165, 166]. Investigators have shown a direct dose-dependent link between increasing amounts of visceral fat and end-organ tissue inflammation and fibrosis in patients with NAFLD demonstrating visceral fat to be directly associated with liver inflammation and scarring in the metabolic syndrome [166, 167]. Importantly, this effect was independent of levels of hepatic steatosis, patient age, and insulin resistance [166, 167]. Ethnic differences in visceral fat are being investigated as potential links to understanding differences in NAFLD. Compared to Caucasians, lower levels of hepatic triglycerides have been found in African Americans despite similar total body adiposity and insulin resistance [166, 168], whilst Asians have increased visceral fat depots in relation to their body mass index (BMI) risking NAFLD despite low BMI [166, 169].
The growing epidemic of obesity across the globe constitutes a major challenge to health services. Nonalcoholic fatty liver disease (NAFLD) has become the most common of all liver disorders with prevalence paralleling the degree of obesity. A clear understanding of the mechanisms underlying disease progression is urgently required to develop prevention and treatment strategies. Adipokines secreted by adipose tissue have recently been implicated in initiating and perpetuating the chronic inflammatory state observed in obesity and NAFLD. Studies should be undertaken to examine the exact role of adipokines derived from intra-abdominal fat as these appear to be the main drivers for the development of progressive liver injury in patients with severe obesity.
References
1. Seidell JC. Epidemiology of obesity. Seminars in Vascular Medicine. 2005;5(1):3–14. [PubMed]
2. The World Health Organization. WHO Technical Report Series 894. Geneva, Switzerland: 2000. Preventing and managing the global epidemic.
3. Kral JG, Schaffner F, Pierson RN, Wang J. Body fat topography as an independent predictor of fatty liver. Metabolism. 1993;42(5):548–551. [PubMed]
4. Ramsey-Stuart G. Hepatic steatosis and morbid obesity. Obesity Surgery. 1993;3(2):157–159. [PubMed]
5. van Steenbergen W, Lanckmans S. Liver disturbances in obesity and diabetes mellitus. International Journal of Obesity. 1995;19(supplement 1):S27–S36. [PubMed]
6. Wolf AM, Busch B, Kuhlmann HW, Beisiegel U. Histological changes in the liver of morbidly obese patients: correlation with metabolic parameters. Obesity Surgery. 2005;15(2):228–237. [PubMed]
7. Youssef WI, McCullough AJ. Steatohepatitis in obese individuals. Best Practice and Research in Clinical Gastroenterology. 2002;16(5):733–747. [PubMed]
8. Festi D, Colecchia A, Sacco T, Bondi M, Roda E, Marchesini G. Hepatic steatosis in obese patients: clinical aspects and prognostic significance. Obesity Reviews. 2004;5(1):27–42. [PubMed]
9. Lyon CJ, Law RE, Hsueh WA. Minireview: adiposity, inflammation, and atherogenesis. Endocrinology. 2003;144(6):2195–2200. [PubMed]
10. Mora S, Pessin JE. An adipocentric view of signaling and intracellular trafficking. Diabetes/Metabolism Research and Reviews. 2002;18(5):345–356. [PubMed]
11. Brunt EM. Nonalcoholic steatohepatitis. Seminars in Liver Disease. 2004;24(1):3–20. [PubMed]
12. Lonardo A. Fatty liver and nonalcoholic steatohepatitis: where do we stand and where are we going? Digestive Diseases. 1999;17(2):80–89. [PubMed]
13. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37(4):917–923. [PubMed]
14. Marceau P, Biron S, Hould FS, et al. Liver pathology and the metabolic syndrome X in severe obesity. Journal of Clinical Endocrinology and Metabolism. 1999;84(5):1513–1517. [PubMed]
15. Alberti KGMM, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. Lancet. 2005;366(9491):1059–1062. [PubMed]
16. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415–1428. [PubMed]
17. Matsuzawa Y, Funahashi T, Nakamura T. Molecular mechanism of metabolic syndrome X: contribution of adipocytokines·adipocyte-derived bioactive substances. Annals of the New York Academy of Sciences. 1999;892:146–154. [PubMed]
18. Unger RH. Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends in Endocrinology and Metabolism. 2003;14(9):398–403. [PubMed]
19. Cases JA, Gabriely I, Ma XH, et al. Physiological increase in plasma leptin markedly inhibits insulin secretion in vivo. Diabetes. 2001;50(2):348–352. [PubMed]
20. Seufert J. Leptin effects on pancreatic β-cell gene expression and function. Diabetes. 2004;53(1):152–158. [PubMed]
21. Zimmet PZ, Alberti KGMM, Shaw J. A new IDF worldwide definition of the metabolic syndrome: the rationale and the results. Diabetes Voice. 2005;50(3):31–33.
22. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. Journal of the American Medical Association. 2002;287(3):356–359. [PubMed]
23. Arner P. Regional adiposity in man. Journal of Endocrinology. 1997;155(11):191–192. [PubMed]
24. Arner P. Differences in lipolysis between human subcutaneous and omental adipose tissues. Annals of Medicine. 1995;27(4):435–438. [PubMed]
25. Wajchenberg BL. Subcutaneous and visceral adipose tissue: Their relation to the metabolic syndrome. Endocrine Reviews. 2000;21(6):697–738. [PubMed]
26. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology. 2004;145(5):2273–2282. [PubMed]
27. Dusserre E, Moulin P, Vidal H. Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues. Biochimica Biophysica Acta. 2000;1500(1):88–96. [PubMed]
28. Lihn AS, Bruun JM, He G, Pedersen SB, Jensen PF, Richelsen B. Lower expression of adiponectin mRNA in visceral adipose tissue in lean and obese subjects. Molecular and Cellular Endocrinology. 2004;219(1-2):9–15. [PubMed]
29. Schaffler A, Scholmerich J, Buchler C. Mechanisms of disease: adipocytokines and visceral adipose tissue—emerging role in nonalcoholic fatty liver disease. Nature Clinical Practice Gastroenterology and Hepatology. 2005;2(6):273–280. [PubMed]
30. Montague CT, Prins JB, Sanders L, et al. Depot-related gene expression in human subcutaneous and omental adipocytes. Diabetes. 1998;47(9):1384–1391. [PubMed]
31. van Harmelen V, Dicker A, Rydén M, et al. Increased lipolysis and decreased leptin production by human omental as compared with subcutaneous preadipocytes. Diabetes. 2002;51(7):2029–2036. [PubMed]
32. Bruun JM, Lihn AS, Madan AK, et al. Higher production of IL-8 in visceral vs. subcutaneous adipose tissue. implication of nonadipose cells in adipose tissue. American Journal of Physiology Endocrinology and Metabolism. 2004;286(1):E8–E13. [PubMed]
33. Bruun JM, Lihn AS, Pedersen SB, Richelsen B. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT. Journal of Clinical Endocrinology and Metabolism. 2005;90(4):2282–2289. [PubMed]
34. Sethi JK, Vidal-Puig A. Visfatin: the missing link between intra-abdominal obesity and diabetes? Trends in Molecular Medicine. 2005;11(8):344–347. [PubMed]
35. Lefebvre AM, Laville M, Vega N, et al. Depot-specific differences in adipose tissue gene expression in lean and obese subjects. Diabetes. 1998;47(1):98–103. [PubMed]
36. Montague CT, Prins JB, Sanders L, Digby JE, O’Rahilly S. Depot- and sex-specific differences in human leptin mRNA expression. Diabetes. 1997;46(3):342–347. [PubMed]
37. Yang RZ, Lee MJ, Hu H, et al. Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action. American Journal of Physiology. 2006;290(6):E1253–E1261. [PubMed]
38. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single topic conference. Hepatology. 2003;37(5):1202–1219. [PubMed]
39. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. American Journal of Gastroenterology. 1999;94(9):2467–2474. [PubMed]
40. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Chang Liu Y, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413–1419. [PubMed]
41. Angelico F, Del Ben M, Conti R, et al. Non-alcoholic fatty liver syndrome: a hepatic consequence of common metabolic diseases. Journal of Gastroenterology and Hepatology. 2003;18(5):588–594. [PubMed]
42. Pagano G, Pacini G, Musso G, et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology. 2002;35(2):367–372. [PubMed]
43. Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35(2):373–379. [PubMed]
44. Freedland ES. Role of a critical visceral adipose tissue threshold (CVATT) in metabolic syndrome: implications for controlling dietary carbohydrates: a review. Nutrition and Metabolism. 2004;1(12):1–24. [PMC free article] [PubMed]
45. Kissebah AH, Krakower GR. Regional adiposity and morbidity. Physiological Reviews. 1994;74(4):761–811. [PubMed]
46. Arner P. Not all fat is alike. Lancet. 1998;351(9112):1301–1302. [PubMed]
47. Kissebah AH, Vydelingum N, Murray R, Evans DJ, Hartz AJ, Kalkhoff RK. Relation of body fat distribution to metabolic complications of obesitof obesity. The Journal of Clinical Endocrinology Metabolism. 1982;54(2):254–260. [PubMed]
48. Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD. Splanchnic lipolysis in human obesity. Journal of Clinical Investigation. 2004;113(11):1582–1588. [PMC free article] [PubMed]
49. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. Journal of Clinical Endocrinology and Metabolism. 2004;89(6):2548–2556. [PubMed]
50. Park KS, Rhee BD, Lee HK, Koh CS, Min HK. Intraabdominal fat is associated with decreased insulin sensitivity in healthy young men. Metabolism. 1991;40(6):600–603. [PubMed]
51. Bergstrom RW, Newell-Morris LL, Leonetti DL, Shuman WP, Wahl PW, Fujimoto WY. Association of elevated fasting C-peptide level and increased intra-abdominal fat distribution with development of NIDDM in Japanese-American men. Diabetes. 1990;39(1):104–111. [PubMed]
52. Couillard C, Bergeron N, Prud’Homme D, et al. Postprandial triglyceride response in visceral obesity in men. Diabetes. 1998;47(6):953–960. [PubMed]
53. Hauner H. Biology of obesity—secretory factors from human adipose tissue and their functional role. Proceedings of the Nutrition Society. 2005;64(2):163–169. [PubMed]
54. Lundgren M, Buren J, Ruge T, Myrnas T, Eriksson JW. Glucocorticoids down-regulate glucose uptake capacity and insulin-signaling proteins in omental but not subcutaneous human adipocytes. Journal of Clinical Endocrinology and Metabolism. 2004;89(6):2989–2997. [PubMed]
55. Giorgino F, Laviola L, Eriksson JW. Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies. Acta Physiologica Scandinavica. 2005;183(1):13–30. [PubMed]
56. Garaulet M, Hernandez-Morante JJ, Lujan J, Tebar FJ, Zamora S. Relationship between fat cell size and number and fatty acid composition in adipose tissue from different fat depots in overweight/obese humans. International Journal of Obesity. 2006:1–7. [PubMed]
57. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. Journal of Clinical Endocrinology and Metabolism. 1998;83(3):847–850. [PubMed]
58. Van Harmelen V, Reynisdottir S, Eriksson P, et al. Leptin secretion from subcutaneous and visceral adipose tissue in women. Diabetes. 1998;47(6):913–917. [PubMed]
59. Van Harmelen V, Rohrig K, Hauner H. Comparison of proliferation and differentiation capacity of human adipocyte precursor cells from the omental and subcutaneous adipose tissue depot of obese subjectss. Metabolism. 2004;53(5):632–637. [PubMed]
60. Wajchenberg BL, Giannella-Neto D, da Silva MER, Santos RF. Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Hormone and Metabolic Research. 2002;34(11-12):616–621. [PubMed]
61. Mohamed-Ali V, Pinkney JH, Coppack SW. Adipose tissue as an endocrine and paracrine organ. International Journal of Obesity. 1998;22(12):1145–1158. [PubMed]
62. Arner P. Regulation of lipolysis in fat cells. Diabetes Reviews. 1996;4(4):450–463.
63. Martin ML, Jensen MD. Effects of body fat distribution on regional lipolysis in obesity. Journal of Clinical Investigation. 1991;88(2):609–613. [PMC free article] [PubMed]
64. Marin P, Andersson B, Ottosson M, et al. The morphology and metabolism of intraabdominal adipose tissue in men. Metabolism. 1992;41(11):1242–1248. [PubMed]
65. Ostman J, Arner P, Engfeldt P, Kager L. Regional differences in the control of lipolysis in human adipose tissue. Metabolism. 1979;28(12):1198–1205. [PubMed]
66. Wahrenberg H, Lonnqvist F, Arner P. Mechanisms underlying regional differences in lipolysis in human adipose tissue. Journal of Clinical Investigation. 1989;84(2):458–467. [PMC free article] [PubMed]
67. Bolinder J, Kager L, Ostman J, Arner P. Differences at the receptor and postreceptor levels between human omental and subcutaneous adipose tissue in the action of insulin on lipolysis. Diabetes. 1983;32(2):117–123. [PubMed]
68. Richelsen B, Pedersen SB, Moller-Pedersen T, Bak JF. Regional differences in triglyceride breakdown in human adipose tissue: effects of catecholamines, insulin, and prostaglandin e2. Metabolism. 1991;40(9):990–996. [PubMed]
69. Rebuffe-Scrive M, Bronnegard M, Nilsson A, Eldh J, Gustafsson JA, Bjorntorp P. Steroid hormone receptors in human adipose tissues. Journal of Clinical Endocrinology and Metabolism. 1990;71(5):1215–1219. [PubMed]
70. Fried SK, Russell CD, Grauso NL, Brolin RE. Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men. Journal of Clinical Investigation. 1993;92(5):2191–2198. [PMC free article] [PubMed]
71. Arner P. Regional differences in protein production by human adipose tissue. Biochemical Society Transactions. 2001;29(2):72–75. [PubMed]
72. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. British Journal of Nutrition. 2004;92(3):347–355. [PubMed]
73. Yudkin JS, Stehouwer CDA, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19(4):972–978. [PubMed]
74. Rajala MW, Scherer PE. Minireview: the adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology. 2003;144(9):3765–3773. [PubMed]
75. Trayhurn P, Wood IS. Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochemical Society Transactions. 2005;33(5):1078–1081. [PubMed]
76. Yudkin JS. Adipose tissue, insulin action and vascular disease: inflammatory signals. International Journal of Obesity. 2003;27(3):S25–S28. [PubMed]
77. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW., Jr. Obesity is associated with macrophage accumulation in adipose tissue. Journal of Clinical Investigation. 2003;112(12):1796–1808. [PMC free article] [PubMed]
78. Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. Journal of Clinical Investigation. 2003;112(12):1821–1830. [PMC free article] [PubMed]
79. Haynes P, Liangpunsakul S, Chalasani N. Nonalcoholic fatty liver disease in individuals with severe obesity. Clinics in Liver Disease. 2004;8(3):535–547. [PubMed]
80. Reid AE. Nonalcoholic steatohepatitis. Gastroenterology. 2001;121(3):710–723. [PubMed]
81. Gramlich T, Kleiner DE, McCullough AJ, Matteoni CA, Boparai N, Younossi ZM. Pathologic features associated with fibrosis in nonalcoholic fatty liver disease. Human Pathology. 2004;35(2):196–199. [PubMed]
82. Charlton M. Nonalcoholic fatty liver disease: a review of current understanding and future impact. Clinical Gastroenterology and Hepatology. 2004;2(12):1048–1058. [PubMed]
83. Abrams GA, Kunde SS, Lazenby AJ, Clements RH. Portal fibrosis and hepatic steatosis in morbidly obese subjects: a spectrum of nonalcoholic fatty liver disease. Hepatology. 2004;40(2):475–483. [PubMed]
84. Zelman S. The Liver in obesity. Archives of Internal Medicine. 1952;90(4):141–156. [PubMed]
85. Adler M, Schaffner F. Fatty liver hepatitis and cirrhosis in obese patients. American Journal of Medicine. 1979;67(5):811–816. [PubMed]
86. Campbell JM, Hunt TK, Karam JH, Forsham PH. Jejunoileal bypass as a treatment of morbid obesity. Archives of Internal Medicine. 1977;137(5):602–610. [PubMed]
87. Kern WH, Heger AH, Payne JH. Fatty metamorphosis of the liver in morbid obesity. Archives of Pathology and Laboratory Medicine. 1973;96(5):342–346. [PubMed]
88. Andersen T, Gluud C. Liver morphology in morbid obesity: a literature study. International Journal of Obesity. 1984;8(2):97–106. [PubMed]
89. Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121(1):91–100. [PubMed]
90. Adamson L, Bell E, Kaye P, Neal K, Ryder SD, Bennett A. Portal inflammtion in non-alcoholic fatty liver disease—is it a marker of a second hit? Hepatology. 2005;42:p. 615A.
91. Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002;123(5):1705–1725. [PubMed]
92. Peters RL, Gay T, Reynolds TB. Post jejunoileal bypass hepatic disease. its similarity to alcoholic hepatic disease. American Journal of Clinical Pathology. 1975;63(3):318–331. [PubMed]
93. Ludwig J, Viggiano TR, McGill DB, Ott BJ. Nonalcoholic steatohepatitis. mayo clinic experiences with a hitherto unnamed disease. Mayo Clinic Proceedings. 1980;55(7):434–438. [PubMed]
94. Seki K, Minami Y, Nishikawa M. “Nonalcoholic steatohepatitis” induced by massive doses of synthetic estrogen. Gastroenterologia Japonica. 1983;18(3):197–203. [PubMed]
95. Novaro GM. Isoniazid and nonalcoholic steatohepatitis. Journal of Clinical Gastroenterology. 1999;28(2):p. 180. [PubMed]
96. Simon JB, Manley PN, Brien JF, Armstrong PW. Amiodarone hepatotoxicity simulating alcoholic liver disease. New England Journal of Medicine. 1984;311(3):167–172. [PubMed]
97. Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology. 1994;107(4):1103–1109. [PubMed]
98. McCullough AJ. Update on nonalcoholic fatty liver disease. Journal of Clinical Gastroenterology. 2002;34(3):255–262. [PubMed]
99. Brallion A, Capron JP, Herve MA, Degot C, Quenum C. Liver in obesity. Gut. 1985;26:133–139. [PMC free article] [PubMed]
100. Garcia-Monzon C, Martin-Perez E, Iacono OL, et al. Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated obesity. Journal of Hepatology. 2000;33(5):716–724. [PubMed]
101. Luyckx FH, Desaive C, Thiry A, Dewe W, Scheen AJ, Gielen JE. Liver abnormalities in severly obese subjects. Effects of drastic weight loss after gastroplasty. International Journal of Obesity. 1998;22:222–226. [PubMed]
102. Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29(3):664–669. [PubMed]
103. Poonawala A, Nair SP, Thuluvath PJ. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology. 2000;32(4 I):689–692. [PubMed]
104. Luyckx FH, Lefebvre PJ, Scheen AJ. Non-alcoholic steatohepatitis: association with obesity and insulin resistance, and influence of weight loss. Diabetes and Metabolism. 2000;26(2):98–106. [PubMed]
105. Day CP, James OFW. Steatohepatitis: a tale of two ’hits’? Gastroenterology. 1998;114(4 I):842–845. [PubMed]
106. Day CP. Non-alcoholic steatohepatitis (NASH): where are we now and where are we going? Gut. 2002;50(5):585–588. [PMC free article] [PubMed]
107. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43(2):99–112. [PubMed]
108. Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37(6):1286–1292. [PubMed]
109. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of non-alcoholic steatohepatitis: a followup study of forty-two patients for up to 21 years. Hepatology. 1990;11:74–80. [PubMed]
110. Sheth SG, Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Annals of Internal Medicine. 1997;126(2):137–145. [PubMed]
111. Sonsuz A, Basaranoglu M, Ozbay G. Relationship between aminotransferase levels and histopathological findings in patients with nonalcoholic steatohepatitis. The American Journal of Gastroenterology. 2000;95(5):1370–1371. [PubMed]
112. Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Human Pathology. 1989;20(6):594–598. [PubMed]
113. Diehl AM, Goodman Z, Ishak KG. Alcohollike liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury. Gastroenterology. 1988;95(4):1056–1062. [PubMed]
114. Cotler SJ, Kanji K, Keshavarzian A, Jensen DM, Jakate S. Prevalence and significance of autoantibodies in patients with non-alcoholic steatohepatitis. Journal of Clinical Gastroenterology. 2004;38(9):801–804. [PubMed]
115. Tajiri K, Takenawa H, Yamaoka K, Yamane M, Marumo F, Sato C. Nonalcoholic steatohepatitis masquerading as autoimmune hepatitis. Journal of Clinical Gastroenterology. 1997;25(3):538–540. [PubMed]
116. Mortele KJ, Ros PR. Imaging of diffuse liver disease. Seminars in Liver Disease. 2001;21(2):195–212. [PubMed]
117. Mottin CC, Moretto M, Padoin AV, et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obesity Surgery. 2004;14(5):635–637. [PubMed]
118. Ataseven H, Yildirim MH, Yalniz M, Bahcecioglu H, Celebi S, Ozercan IH. The vaue of ultrasonography and computerized tomograph in estimating the histopatological severity of nonalcoholic steatohepatitis. Gastroenterology in Belgium. 2005;68:221–225. [PubMed]
119. Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123(3):745–750. [PubMed]
120. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30(6):1356–1362. [PubMed]
121. Joy D, Thava VR, Scott BB. Diagnosis of fatty liver disease: is biopsy necessary? European Journal of Gastroenterology and Hepatology. 2003;15(5):539–543. [PubMed]
122. Siegelman ES, Rosen MA. Imaging of hepatic steatosis. Seminars in Liver Disease. 2001;21(1):71–80. [PubMed]
123. Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Seminars in Liver Disease. 2001;21(1):3–16. [PubMed]
124. Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an evolving diagnosis. Canadian Journal of Gastroenterology. 2000;14(4):321–326. [PubMed]
125. Shimada M, Hashimoto E, Taniai M, Hasegawa K, Okuda H, Nakanuma Y. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. Pathology International. 2001;51:127–131. [PubMed]
126. Moretto M, Kupski C, Mottin CC, et al. Hepatic steatosis in patients undergoing bariatric surgery and its relationship to body mass index and co-morbidities. Obesity Surgery. 2003;13(4):622–624. [PubMed]
127. Shalhub S, Parsee A, Gallagher SF, et al. The importance of routine liver biopsy in diagnosing nonalcoholic steatohepatitis in bariatric patients. Obesity Surgery. 2004;14(1):54–59. [PubMed]
128. Campbell MS, Reddy KR. Review article: the evolving role of liver biopsy. Alimentary Pharmacology and Therapeutics. 2004;20(3):249–259. [PubMed]
129. Hubscher SG. Role of liver biopsy in the assessment of non-alcoholic fatty liver disease. European Journal of Gastroenterology and Hepatology. 2004;16(11):1107–1115. [PubMed]
130. Bravo AA, Sheth SG, Chopra S. Liver biopsy. New England Journal of Medicine. 2001;344(7):495–500. [PubMed]
131. Merriman RB, Ferrel LD, Patti MG, Ostroff JW, Bagetelos K, Aouizerat BE. Histologic correlation of paired right lobe and left lobe liver biopsies in morbidly obese individuals with suspected nonalcoholic fatty liver disease. Hepatology. 2003;38(supplement 1):p. 230A.
132. Grant A, Neuberger J. Guidelines on the use of liver biopsy in clinical practice. Gut. 1999;45(supplement 4):1–11. [PMC free article] [PubMed]
133. Guido M, Rugge M. Liver biopsy sampling in chronic viral hepatitis. Seminars in Liver Disease. 2004;24(1):89–97. [PubMed]
134. Geller S, Pitman M. Morphological diagnostic procedures (liver biopsy) In: Burt AD, Portmann BC, McSween RNM, editors. Pathology of the Liver. London, UK: Churchill Livingston; 2002:. pp. 943–960.
135. Seki S, Sakaguchi H, Kadoya H, et al. Laparoscopic wedge biopsy of the liver with use of an ultrasonically activated scalpel. Digestive Endoscopy. 2001;13(1):17–20.
136. Gilmore IT, Burroughs A, Murray-Lyon IM, Williams R, Jenkins D, Hopkins A. Indications, methods, and outcomes of percutaneous liver biopsy in England and Wales: an audit by the British Society of Gastroenterology and the Royal College of Physicians of London. Gut. 1995;36(3):437–441. [PMC free article] [PubMed]
137. Piccinino F, Sagnelli E, Pasquale G. Complications following percutaneous liver biopsy. Journal of Hepatology. 1986;2(2):165–173. [PubMed]
138. Colloredo G, Guido M, Sonzogni A, Leandro G. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. Journal of Hepatology. 2003;39(2):239–244. [PubMed]
139. Maharaj B, Maharaj RJ, Leary WP. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet. 1986;1(8480):523–525. [PubMed]
140. Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. American Journal of Gastroenterology. 2003;98(9):2042–2047. [PubMed]
141. Fassio E, Alvarez E, Domínguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology. 2004;40(4):820–826. [PubMed]
142. Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I. Liver fibrosis in over weight patients. Gastroenterology. 2000;118:1117–1123. [PubMed]
143. Propst A, Propst T, Zangerl G, Ofner D, Judmaier G, Vogel W. Prognosis and life expectancy in chronic liver disease. Digestive Diseases and Sciences. 1995;40(8):1805–1815. [PubMed]
144. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123(1):134–140. [PubMed]
145. Clark JM, Diehl AM. Nonalcoholic fatty liver disease. An underrecognized cause of cryptogenic cirrhosis. Journal of the American Medical Association. 2003;289(22):300–304. [PubMed]
146. McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clinics in Liver Disease. 2004;8(3):521–533. [PubMed]
147. Dixon JB, Bhathal PS, Hughes NR, O’Brien PE. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology. 2004;39(6):1647–1654. [PubMed]
148. Eriksson S, Eriksson KF, Bondesson L. Nonalcoholic steatohepatitis in obesity: a reversible condition. Acta Medica Scandinavica. 1986;220(1):83–88. [PubMed]
149. Andersen T, Gluud C, Franzmann MB, Christoffersen P. Hepatic effects of dietary weight loss in morbidly obese subjects. Journal of Hepatology. 1991;12(2):224–229. [PubMed]
150. Luyckx FH, Scheen AJ, Desaive C, Dewe W, Gielen JE, Lefebvre PJ. Effects of gastroplasty on body weight and related biological abnormalities in morbid obesity. Diabetes and Metabolism. 1998;24(4):355–361. [PubMed]
151. Drenick EJ, Simmons F, Murphy JF. Effect on hepatic morphology of treatment of obesity by fasting, reducing diets and small-bowel bypass. New England Journal of Medicine. 1970;282(15):829–834. [PubMed]
152. Tilg H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. New England Journal of Medicine. 2000;343(20):1467–1476. [PubMed]
153. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-α or adiponectin? Hepatology. 2004;40(1):46–54. [PubMed]
154. Choi S, Diehl AM. Role of inflammation in nonalcoholic steatohepatitis. Current Opinion in Gastroenterology. 2005;21(6):702–707. [PubMed]
155. Atzmon G, Yang XM, Muzumdar R, Ma XH, Gabriely I, Barzilai N. Differential gene expression between visceral and subcutaneous fat depots. Hormone and Metabolic Research. 2002;34(11-12):622–628. [PubMed]
156. Lyon CJ, Law RE, Hsueh WA. Minireview: adiposity, inflammation, and atherogenesis. Endocrinology. 2003;144(6):2195–2200. [PubMed]
157. Ziccardi P, Nappo F, Giugliano G, et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation. 2002;105(7):804–809. [PubMed]
158. Lehrke M, Reilly MP, Millington SC, Iqbal N, Rader DJ, Lazar MA. An inflammatory cascade leading to hyperresistinemia in humans. PLoS Medicine. 2004;1:161–168. [PMC free article] [PubMed]
159. Chitturi S, Farrell G, Frost L, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology. 2002;36(2):403–409. [PubMed]
160. Chalasani N, Crabb DW, Cummings OW, et al. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? American Journal of Gastroenterology. 2003;98(12):2771–2776. [PubMed]
161. Angulo P, Alba LM, Petrovic LM, Adams LA, Lindor KD, Jensen MD. Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease. Journal of Hepatology. 2004;41(6):943–949. [PubMed]
162. Musso G, Gambino R, Durazzo M, et al. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology. 2005;42(5):1175–1183. [PubMed]
163. Czaja MJ. Liver injury in the setting of steatosis: crosstalk between adipokine and cytokine. Hepatology. 2004;40(1):19–22. [PubMed]
164. Janke J, Angeli S, Gorzelniak K, Luft FC, Sharma AM. Resistin gene expression in human adipocytes is not related to insulin resistance. Obesity Research. 2002;10(1):1–5. [PubMed]
165. Pagano C, Soardo G, Pilon C, et al. Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance. Journal of Clinical Endocrinology and Metabolism. 2006;91(3):1081–1086. [PubMed]
166. Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease. Annual Review of Pathology. 2010;5:145–171. [PubMed]
167. Van Der Poorten D, Milner KL, Hui J, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008;48(2):449–457. [PubMed]
168. Guerrero R, Vega GL, Grundy SM, Browning JD. Ethnic differences in hepatic steatosis: an insulin resistance paradox? Hepatology. 2009;49(3):791–801. [PMC free article] [PubMed]
169. Weston SR, Leyden W, Murphy R, Bass NM, Bell BP. Racial and ethnic distribution ofnonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology. 2005;41:372–379. [PubMed]
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