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Review article
Evolving trends in nonalcoholic fatty liver disease
Jorge-Shmuel Delgado ⁎
The University of Chicago, Section of Gastroenterology, Department of Medicine, Chicago, 5841 S. Maryland Ave., MC 4076 Chicago, IL 60637, USA
Received 7 July 2006; received in revised form 26 October 2006; accepted 9 February 2007

Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common etiologies of chronic liver disease worldwide. NALFD encompasses a continuum of histological findings ranging from steatosis alone, to nonalcoholic steatohepatitis (NASH) with steatosis,inflammation, hepatocyte ballooning, fibrosis and eventually liver cirrhosis. The pathogenesis of NAFLD might be related to a deregulatedcross-talk between liver and visceral adipose tissue, originating an impairment of normal insulin signaling. A better comprehension of the immunologic and metabolic roles of adipose tissue in modulating inflammatory pathways will enhance our understanding of the molecular mechanisms leading to progression of fatty liver disease. These insights, moreover, will suggest new strategies to improve insulin sensitivity and reduce obesity-associated morbidities and mortality.
© 2007 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Keywords: Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Insulin resistance; Visceral adipose tissue; Metabolic syndrome

1. Introduction
Nonalcoholic fatty liver disease (NAFLD) is one of the most common etiologies of chronic liver disease worldwide [1–3]. In the United States, NAFLD is themost frequent cause of asymptomatic abnormal liver function tests, affecting an estimated 30 million Americans [4–6]. NALFD encompasses a continuum of histological findings ranging from steatosis alone, to nonalcoholic steatohepatitis (NASH) with inflammation, hepatocyte ballooning and fibrosis [7]. The latter condition is at risk to progress eventually to cirrhosis [8–11].

2. Pathophysiology
The pathogenesis of NAFLD remains incompletely understood.
The most accepted model implicates insulin resistance as a key mechanism leading to liver steatosis via increases in delivery of free fatty acids to the liver, as the “first hit”. It is postulated that a “second hit,” involving oxidative injury, is required to elicit the lobular inflammatory component of steatohepatitis [12]. Nevertheless, it is poorly understood why steatosis remains stable in many patients, whereas the disease
advances to fibrosis and even cirrhosis in others. NAFLD is strongly associated with the metabolic syndrome, a well-established clinical constellation of central obesity, type 2 diabetes mellitus, arterial hypertension and dyslipidemia in a common pathophysiologic background of insulin resistance [13–16]. The strong associations of obesity and type 2 diabetes mellitus with NAFLD have suggested that
these conditions contribute to the pathogenesis of liver injury by enhancing insulin resistance, steatosis and progression to steatohepatitis [13,15,17,18]. This underlying susceptibility to develop fatty liver in the
context of obesity is incompletely understood. Recent studies suggest that central obesity is a chronic, ongoing systemic lowgrade inflammatory condition [19]. In contrast to previous notions that fat tissue was a metabolically inactive site of energy storage, it is increasingly clear that visceral adipose tissue is a highly complex tissue ofmultiple cells types engaged in diverse endocrine, metabolic and immunologic functions.
Fat tissue secretes many potentially pro-inflammatory cytokines [20]. These include active secretion from adipocytes of numerous cytokines such as tumor necrosis factor (TNFα), interleukin 6 (IL-6), interleukin 8 (IL-8), plasminogen activator inhibitor (PAI), angiotensinogen, leptin, resistin, adiponectin, denoted collectively as adipokines or adipocytokines. The relationships of these cytokines to visceral fat and to obesity-related liver injury are areas of intense research. Somehow, obesity defined commonly by a
body mass index (BMI) greater than 30 kg/m2 is not an essential requirement for the development of steatohepatitis. It appears that visceral fat is a better predictor for insulin resistance and liver dysfunction [21,22]. Adipose tissue macrophages are located predominantly in the visceral adipose tissue (VAT). These cells are recruited by nuclear factor-κB (NF-κB)-dependent increases in monocyte
chemoattractant protein (MCP-1). Macrophage cells appear to play a key role in mediating systemic inflammation associated with obesity via induction of Th-1 type cytokine responses and expression of other pro-inflammatory genes [23–27]. Increased secretion of TNFα and other adipocytokines
associated with obesity and concomitant decreases in fatderived hormone adiponectin may suppress the function of hepatic genes that regulate normal fatty acid oxidative metabolism. These pro-inflammatory cytokines may also activate genes involved in de novo lipogenesis, other inflammatory pathways and oxidative liver stress [28–30]. In summary, deregulated cross-talk between liver and visceral adipose tissue may cause impairment of normal insulin signaling, and lead to other metabolic and immunologic
derangements that drive the development of steatohepatitis.

3. Epidemiology
The prevalence of NAFLD and NASH in obese patients ranges from 69 to 100% and 25 to 30% of cases respectively [31–34]; whereas in a non-selected population the incidences of these disorders aremuch lower,with estimates of 12–15%of the population having NAFLD, and 3–4% has NASH [2,6].
Since the prevalence of obesity has been rising sharply in recent years, it is estimated that NASH and its related complications, will approach epidemic proportions in the western countries. In Europe, the recent Dionysos Nutrition and Liver crosssectional study in a general population of a Northern Italian
town, has demonstrated a similar prevalence ofNAFLD as has been reported in Western countries [35]. Also, the prevalence of fatty liver in this study was similar in patients with and without suspected liver disease (25% VS. 20%). Furthermore there was an association with the metabolic syndrome [35].
Another epidemiological study coming from Southern Italy pointed out that NAFLD was linked to several features of the metabolic syndrome and was the probable etiology of elevated liver enzymes in 24% of the general population [36]. In addition to the metabolic syndrome, there are other conditions which sporadically have been linked to NAFLD, comprising total parental nutrition, extensive small bowel
resection, bacterial overgrowth, starvation and drugs [37,38]. Amiodarone, tamoxifen, estrogen, steroids and some protease inhibitors are examples of drugs related with steatohepatitis [38]. These cases may resemble the histopathology of NAFLD but maybe, from a semantic standpoint, could be better redefined as secondary steatohepatitis or drug-induced steatohepatitis respectively.

4. Natural history
The natural history appears to be quite variable. In general, there is an increase of the mortality rate in patients with NAFLD in comparison to the universal population [10,39]. The rate of progression is prominently linked to the liver necroinflammatory and fibrosis severity. Patients with fatty liver alone have usually a relatively benign clinical course, with 1.5% to 3% developing advanced liver fibrosis
[7,8,40]. However, liver cirrhosis has been reported in 15% to 25% of NASH patients, with a 30% to 40% liver-related mortality over a 10-year period [40–42]. This is rather similar to the mortality reported with other major causes of liver cirrhosis [43]. Additionally, NASH has been recognized as a frequent
etiology of “cryptogenic” cirrhosis, with burn-out of the steatohepatitis histologic findings once the cirrhosis appears [44]. The NASH-associated cirrhosis accounts for approximately of 13% of all cases of hepatocellular carcinoma [45,46]. Finally, the presence of NAFLD-NASH could be an additive factor to liver injury in the context of other hepatotoxic factors such as drugs, toxins and viruses [47,48].

5. Diagnosis
5.1. Clinical and laboratory features
The evaluation of patients with possible NAFLD or NASH should include assessment of features of metabolic syndrome and excluding significant alcohol consumption (more than 40 g of ethanol per week), since NAFLD is usually asymptomatic [49–51]. If, any, fatigue and discomfort in the right upper quadrant of the abdomen, are the main complaints [49– 51].On physical examination, hepatomegalymight be present, but in general other signs of chronic liver disease are rare, unless the patient presents with well-established cirrhosis [49,50].
Normal serum aminotransferases do not exclude the presence of advanced histologic features [50,51]. Furthermore, liver enzyme levels have been reported to be normal in up to 78% of patients at any given time [51]. Once liver enzymes are elevated, which eventually occurs in almost 90% of the
cases, increases are mild (defined as less than 250 U/L) of one or both of the alanine and aspartate aminotransferases (ALT and AST respectively). The AST/ALT ratio is typically less than 1. Several authors have reported mild and non-specific elevation of gamma-glutamyltransferase and ferritin in some
patients [52], as well as the presence of autoantibodies in about 25% of patients diagnosed with NAFLD [53]. 76 J.-S. Delgado / European Journal of Internal Medicine 19 (2008) 75–82

5.2. Imaging
Ultrasonography, computed tomography, magnetic resonance scanning and magnetic resonance spectroscopy have been used increasingly for detecting fatty liver [54]. Liver ultrasound is perhaps the most popular modality for the diagnosis of NAFLD, mainly as a result of its lower cost and wide
accessibility in medical practice [54].Ultrasonographic findings of “bright” liver, with increased echogenicity compared with the kidneys, vascular blurring and deep attenuation are suggestive
of liver steatosis. The sensibility and specificity of liver ultrasound are between 60 and 94% and 88 and 95%respectively for detecting liver steatosis [54]. Notwithstanding, both sensibility and specificity aremuch lower in obese patientswith bodymass index (BMI) greater than 40 kg/m2 [54].
None of these imaging modalities could clearly distinguish between fatty liver alone and NASH, nor predict the degree of liver fibrosis [7,54].

5.3. Liver biopsy
Liver biopsy remains the gold standard for diagnosis, staging and grading NAFLD [9–11]. Themajormorphological features are strikingly similar to alcohol-induced liver injury;
however NALFD arises in patients with no significant history of ethanol consumption [7–11]. The contribution of liver biopsy to confirm the clinical diagnosis, excluding other liver diseases and monitoring disease progression is beyond any doubt [55–57]. However, it is an invasive procedure, with a definite although low risk of serious complications. Additionally, it could lead to a misinterpretation of the degree of fibrosis due to sampling error and interobserver variability,with the consequent understaging of cirrhosis [56,57]. Therefore, the decision to perform a liver biopsy should be made on an individual basis, after careful discussion with the patient. Liver biopsy should be recommended especially if there are strong
predictors of liver fibrosis, i.e. age over 45, BMI N30, type 2 diabetesmellitus,AST:ALTratio N1, triglycerides≥1.7mmol/ L and an ALT concentration twice the normal range [7,58].
As a result of these limitations and the fact that most patients with NAFLD are asymptomatic, there has been recent interest in several non-invasive methods which aim to predict fibrosis and cirrhosis [59]. Among them, the direct biomarkers of fibrosis and transient elastography have drawn the most
attention [60–62]. Hyaluronic acid and type collagen IV are the main biomarkers of liver fibrosis studied in small cohorts of patients with NAFLD [60,61]. In general the evidence supporting their role in
discriminating remarkable from insignificant fibrosis could be considered encouraging, with a sensitivity ranging from 66 to 85, specificity 68 to 91 and a reported area under the curve ranging from 0.78 to 0.87. Further studies are needed to support the routine use of these markers in patients with fatty liver.
Transient elastography (Fibroscan) is the second noninvasive method in the evaluation of liver fibrosis which has been reported in patients with NAFLD [62]. It is based in the measurement of liver stiffness as an expression of fibrosis. The reported values of liver stiffness in cirrhotic patients ranged from 12.5 to 75.4 kPa [62]. However, a recent study has reported bymultivariate analysis that a bodymass index (BMI) greater than 28 is a factor associated with Fibroscan failure to measure properly the liver stiffness [63]. Thus it could be considered a serious drawback if we bear in mind that NAFLD and obesity are intrinsically associated. Therefore, these methods can not yet be considered as a substitute of liver biopsy.

6. Management
The therapeutic arsenal for patients with NASH, although restricted, has been evolving in the last years. The treatment approaches have been based on modification of underlying risk factors, use of hepatoprotective agents including antioxidants, lipid-lowering drugs and finally the more promising,
insulin sensitizing drugs.

6.1. Weight reduction
Since NAFLD is strikingly associated with obesity and metabolic syndrome, attempts to achieve strict metabolic control should be emphasized by changing dietary habits and lifestyle modification. Unfortunately, the evidence supporting this strategy has been far from definitive, mostly based
on small and older case studies. Nevertheless, during the last 3 years, several rigorous investigations
have been published. These studies support the role of pharmacological [64–69] and surgical weight loss strategies [70–77] in obese patients with BMI greater than 40 kg/m2 or greater than 35 kg/m2 in association with co-morbidities. These studies have more consistently reported biochemical and liver
histological improvements (Tables 1 and 2). A target of 10% to 20% of baseline body weight as an
initial goal for weight loss has been an historical endpoint, particularly due to concern raised in early studies regarding increased liver fibrosis with drastic or rapid weight loss [78]. However, recent data, coming from several groups, have challenged this recommendation, reporting more aggressive weight loss approaches, without evidence of worsening in the necroinflammatory and fibrosis scores [73–77].

6.2. Antioxidant
Mitochondrial dysfunction as a result of an uncontrolled oxidative stress and TNFα over expression might be a key factor in the “second hit” hypothesis with the consequent hepatocellular apoptosis and necrosis. Thus, several studies with “cytoprotective” and “antioxidant” drugs have been published, including those with vitamin E [79–81], vitamin C [81], betaine [82] and ursodeoxycholic acid [83]. Several inconsistent results have been published with vitamin E [79–81]. In the first small open-label study, a trial of
vitamin E (400–1200 IU/day) during 4–10 months in a case series of 11 children diagnosed with NAFLD, led to a J.-S. Delgado / European Journal of Internal Medicine 19 (2008) 75–82 77

significant improvement in liver enzymes when compared with baseline values [79]. Kugelmas reported the results of a pilot study, using a step 1 American Heart Association diet plus aerobic exercisewith orwithout 800 IUof vitamin E daily in 16 patients with biopsy-proven NASH for 6 weeks. Followup
biochemical assessment included cytokine profiles (TNF, IL-8, IL-6) and liver enzyme levels. Cytokine values generally did not decrease significantly with weight loss with or without vitamin E over the duration of the study. Liver enzymes decreased with lifestyle modifications (low-fat diet and exercise), but no additive effect was associated with vitamin E [80]. Similarly, a recent randomized, double-blind, placebo-controlled trial with vitamin E (1000 IU/day) combined with C (1000 mg/day) for 6 months was no better than placebo for patients with NASH [81]. Surprisingly, compared with baseline values, a statistically significant improvement in serum levels of ALT was seen in the placebo group, but not in
the vitamin E group [81]. Further, a prospective, randomized double-blind, placebocontrolled
trial, in patients affected with NASH, compared ursodeoxycholic acid (UDCA) at a dose of 13–15 mg/kg/day versus placebo, for a period of 2 years and failed to show any substantial biochemical or histological difference between

the UDCA and placebo groups [83]. Summing up, current
data is lacking to support the use of these agents.

6.3. Lipid-lowering drugs
As dyslipidemia is one of the components of metabolic syndrome associated to NAFLD, statins and fibrate drugs have been considered as possible treatments for this hepatic disorder. Mostly, small published studies with gemfibrozil [84], probucol [85], pravastatin [86] and artovastatin [87], have demonstrated noteworthy biochemical improvements, with no available data concerning the liver histology. We urgently need better and larger controlled trials to elucidate the role of these drugs in NAFLD.

6.4. Down-regulation of the insulin resistance mechanism
Insulin resistance is believed to play potential crucial role in the pathogenesis ofNAFLD. Consequently, insulin sensitizing drugs are being extensively investigated as a potential “future arsenal of choice” for this metabolic liver complication. Metformin reduces the hyperinsulinemia and the insulin resistance by down-regulating the hepatic glucose output and increasing the mitochondrial β-oxidation. In non-diabetic
children with biopsy-proven nonalcoholic steatohepatitis, an open-label trial with metformin (500 mg twice daily for 24 weeks) was notable for improvement in liver chemistry, liver fat, insulin sensitivity and quality of life [88]. In adults, a randomized trial, comparing metformin (850 mg twice a day for 6 months) plus diet versus dietary treatment alone in 36 patients with nonalcoholic steatohepatitis resulted in significant
decrease of ALT/AST, insulin and C-peptide levels from baseline in the group given metformin. The mean changes in these parameters in the metformin group were significantly greater than those in the group given dietary treatment alone. Although more patients in the metformin group showed improvement in the necroinflammatory activity, compared with the group given dietary treatment alone, no significant differences in necroinflammatory activity or fibrosis were seen between the groups [89].
In a more recent open-label trial, 110 non-diabetic NAFLD patients were randomized to several arms: metformin (2 g/day; n=55) or vitamin E (800 IU/day; n=28) or were treated by a weight-reducing diet (n=27) for 1 year. Aminotransferase levels improved in all groups, in association with weight loss but this decrease was more prominent in the metformin arm (odds ratio versus controls, 3.11; 95% confidence interval (CI), 1.56–6.20; P=0.0013). The distribution of positive criteria for the metabolic syndrome
was reduced only in the metformin arm (P=0.001). A second biopsy at the end of follow-up, in metformin-treated cases who did not achieve a complete normalization of ALT levels,
showed a significant decrease in liver fat, necroinflammation and fibrosis degree, in comparison with the histological diagnosis at baseline. Additionally no side effects were observed during metformin treatment [90].

6.5. Thiazolinediones
Increasing interest has focused on the therapeutic potential of peroxisome proliferation-activated receptor-γ (PPAR-γ) agonist, commonly known as “glitazones” in the context of NAFLD. Thiazolidinediones (TZDs) noticeably enhance insulin sensitivity. TZDs also decrease the “fatty liver” lipid-profile by increasing fatty acid uptake in peripheral adipose tissue through activation of PPAR-gamma receptors
and up-regulation of adiponectin expression. The evidence supporting the use of TZDs in NASH is very
encouraging. A reported clinical trial with rosiglitazone, 4 mg twice daily for 48 weeks in 30 adults with prior biopsy evidence of NASH demonstrated a significant improvement in the mean global necroinflammatory and fibrosis score compared to the liver biopsy baseline score. Furthermore
biopsies of 10 patients (45%) no longer met published criteria for NASH after treatment. Additionally, 84% of the patients who completed 48 weeks of treatment had significant improvements with regard to insulin sensitivity and mean ALT levels.Weight gain (averaging 7.3%) was the major side effect of rosiglitazone [91]. A more recent randomized prospective trial comparing the efficacy and safety of vitamin E alone (400 IU/day, n=10) versus vitamin E (400 IU/day) and pioglitazone (30 mg/day)
(n=10) during 24 weeks in non-diabetic, non-cirrhotic subjects with NASH, culminated in a significant decrease in steatosis (mean, 2.3 vs. 1; Pb0.002), cytologic ballooning (1.3 vs. 0.2; Pb0.01), Mallory's hyaline (0.7 vs. 0.2; Pb0.04), and pericellular fibrosis (1.2 vs. 0.6; Pb0.03) in the combined pioglitazone and vitamin E arm, in comparison to the group treated with vitamin E alone [92]. Another clinical trial with 18 non-diabetic patients with NASH, treated with pioglitazone (30 mg daily) for 48 weeks, who underwent liver biopsy pre and post treatment, showed a significant fall in ALT values to normal levels in 72% of patients. Glucose and free fatty acid sensitivity to insulin were uniformly improved. Even more striking was the fact that histological features of steatosis, cellular injury, parenchymal inflammation and fibrosis were significantly improved from baseline (all Pb0.05) in two-thirds of patients. Pioglitazone was well tolerated; the major side effects were weight gain (averaging 4%), and an increase in total body
adiposity [93]. The long-term benefits of the PPAR-γ agonists drugs and metformin in NASH have not been established yet. There are currently two clinical trials addressing this important question. The first one is the “Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis” (PIVENS) trial with a planned enrollment of 240 non-diabetic patients over 2 years into one of three treatment groups. The second trial is the “Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in Children” (TONIC) trial that will enroll 180 children with NAFLD to receive vitamin E, metformin, or placebo over 18 months. The results of these studies are eagerly awaited.
J.-S. Delgado / European Journal of Internal Medicine 19 (2008) 75–82 79

 

7. Conclusions
A better comprehension of the immunologic and metabolic roles of adipose tissue in modulating inflammatory pathways will enhance our understanding of the molecular mechanisms
that drive NAFLD and NASH. These insights, moreover, will likely suggest new strategies to improve insulin sensitivity and reduce obesity-associated morbidities and mortality.

8. Learning points
• NAFLDis usually associated with themetabolic syndrome. • The diagnosis of NASH, as opposed to fatty liver alone, can only be made by a liver biopsy. The need for a liver biopsy should be individualized.
• Treatment should be focused on correction of the underlying metabolic syndrome.
• The role of insulin sensitizing drugs continues to evolve. Acknowledgements
The author is grateful to Dr. Marc B. Bissonnette and Professor Jerome B. Taxy, for their kind review and analysis of this article. This study has been supported by Dr. Moshe B. Goldgraber Advanced Fellowship in Digestive diseases.