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Author - Z. M. Younossi
Aliment Pharmacol Ther.2008;28(1):2-12
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome.
Aim: To assess the epidemiological impact and the current management of patients with NAFLD.
Methods: Published peer-reviewed literature and abstracts concerning NAFLD and non-alcoholic steatohepatitis (NASH) were reviewed. Articles specifically related to epidemiology, diagnosis and current treatment strategies for NAFLD and NASH are summarized.
Results: NAFLD is strongly associated with the epidemic of obesity and type-2 diabetes mellitus, and is estimated to affect about 20-30% of the population in the US. From the spectrum of NAFLD, only patients with biopsy-proven NASH (estimated prevalence in the US population is about 3-5%) have been convincingly shown to progress to cirrhosis, liver failure and hepatocellular carcinoma. The clinical manifestation of NAFLD is usually absent or subtle, with abnormal aminotransferases or incidental radiographic findings of fatty liver. The pathogenesis of NAFLD is attributed to a multi-hit process involving insulin resistance, oxidative stress, apoptotic pathways, and adipocytokines. In 2008, there is no established treatment for NAFLD. Weight loss and treatment for each component of metabolic syndrome. Nevertheless, a large number of agents are being considered in clinical trials of patients with NASH.
Conclusions: Awareness of the tremendous impact of NAFLD as an important cause of chronic liver disease is increasing along with a great deal of information about its pathogenesis. Future, well-designed clinical trials that target specific pathways involved in the pathogenesis of NASH are urgently needed.
Introduction
Non-alcoholic steatohepatitis (NASH) was first described more than two decades ago and is now considered part of a spectrum of non-alcoholic fatty liver diseases (NAFLD). NASH resembles alcoholic steatohepatitis (ASH), but occurs in individuals who do not consume excessive amounts of alcohol. Both the more encompassing NAFLD and its progressive subtype, NASH, are considered to be the hepatic manifestation of metabolic syndrome.[1]
Non-alcoholic fatty liver disease is the most common cause of chronic liver disease in the US.[2-5] The estimated prevalence of NAFLD is 20-30% and for NASH it is estimated at 3.5-5%.[6-9] NAFLD occurs in patients of both genders, all ethnicities and in all age groups, including children.[7,9-11] Nonetheless, when compared with non-Hispanic whites, NAFLD seems to be more prevalent among Hispanics and less prevalent among non-Hispanic blacks.[7,9-11]
In addition to the high prevalence of NAFLD, its potential to progress has an important impact; NAFLD subtypes differ in their potential for progression. Although most patients with simple steatosis do not progress, 10-15% with histologically proven NASH do progress to cirrhosis and its complications such as liver failure, and hepatocellular carcinoma. These rates were initially reported by tertiary care institutions, but have been confirmed by more rigorous studies that have examined sequential liver biopsies and community cohort data.[12-14] A long-term follow-up study of NAFLD patients showed that patients with NASH have lower survival rates.[13] Additionally, most of the patients in the follow-up period developed type-2 diabetes or impaired glucose tolerance.[13] Finally, a recent population study based on the NHANES III database showed that subjects with a presumed diagnosis of NAFLD have higher liver-related and all-cause mortality than those without liver disease.[15] Another line of evidence suggesting a progressive course for NASH comes from data obtained from patients with the diagnosis of cryptogenic cirrhosis, which accounts for about 10% of liver transplants. Most cases of cryptogenic cirrhosis in the US are regarded as ‘burned out NASH’.[5,9]
In short, both the prevalence and natural history of NAFLD suggest that it is a very common cause of liver disease and that its subtype, NASH, can progress to cirrhosis. These observations underscore the significant impact of NAFLD in terms of patient health, health-related quality of life and healthcare economics.[16,17]
Clinical Presention and Diagnosis
As previously noted, NAFLD is the hepatic manifestation of metabolic syndrome. In fact, risk factors associated with NAFLD include central obesity, type-2 diabetes mellitus, insulin resistance (IR) and dyslipidemia. Furthermore, other metabolic conditions accompanied by similar biochemical abnormalities, such as polycystic ovary syndrome and lipodystrophy, are strongly associated with NAFLD.[18,19]
It is important to remember that NAFLD remains a diagnosis of exclusion, so other causes of chronic liver disease must be ruled out, especially alcoholic liver disease, HCV and Wilson's disease (in young patients). Of these conditions, the exclusion of excessive alcohol use is especially crucial and challenging. As previously noted, NASH resembles ASH histologically. Therefore, it is important to obtain an accurate history of alcohol intake, including the daily quantity of alcohol consumption. The threshold for excessive alcohol use for female patients is <10 g of alcohol per day and for male patients, no more than 20 g/day.[19] However, consumption of even lower amounts of alcohol may contribute to liver disease in patients with other risk factors such as obesity, metabolic syndrome, viral hepatitis and other chronic liver diseases.
Non-alcoholic fatty liver disease patients are generally asymptomatic with mild, fluctuating elevations in their liver enzymes. The most common laboratory abnormality is mild to moderate elevations in aminotransferases - two to five times the upper limits of normal. A few patients with NAFLD may present with malaise, fatigue and right upper quadrant abdominal pain and, rarely, their physical examination may reveal hepatomegaly.[1,12,19-22]
Radiological modalities are used extensively to diagnose NAFLD because clinical and laboratory tests are nonspecific. However, ultrasound (US), computerized tomography (CT) and magnetic resonance imaging (MRI) are able to detect hepatic steatosis, but they are not able to differentiate the nonprogressive form of NAFLD (simple steatosis) from the potentially progressive form (NASH).[23-28] Saadeh et al. examined the ability of different radiological modalities to distinguish between NASH and less progressive forms of NAFLD.[23] Twenty-five patients with NAFLD underwent simultaneous radiological assessments with ultrasonography, CT and MRI within 3 months after liver biopsy. None of the radiological features in these protocols could distinguish patients with the pathological diagnosis of NASH from those with simple steatosis. Ultrasonography and CT were 100% and 93% sensitive in detecting >33% fat, with positive predictive values of 62% and 72%, respectively. This study shows that despite excellent sensitivity in detecting significant steatosis, these modalities are not capable of distinguishing between NASH and other forms of NAFLD.[23]
Because of the limitations in clinical, laboratory, and radiological tests, liver biopsy remains the gold standard for the definitive diagnosis of NAFLD and NASH. Histologically, NAFLD is indicated by the presence of fatty infiltration of the liver, defined as exceeding 5% of hepatocytes.[29,30] The minimum histological criteria for NASH include hepatic steatosis, mixed lobular inflammation and hepatocellular ballooning.[12,13,31,32] Other pathological findings such as Mallory bodies or perisinusoidal fibrosis can make the diagnosis even stronger.
Despite its usefulness in establishing the diagnosis of NASH and staging hepatic fibrosis, liver biopsy has several important limitations. First, liver biopsy remains costly and is associated with potentially important complications. Second, liver biopsy can be associated with sampling error. In fact, the negative predictive value of a single biopsy for the diagnosis of NASH is estimated at 74%. Finally, an inadequate length or fragmented biopsy specimen can make the correct diagnosis even more challenging.[32-34]
Alternatives to liver biopsy include non-invasive radiological modalities such as US, CT and MRI, but as noted earlier, routine radiological modalities are incapable of distinguishing NASH or stage of fibrosis. Another non-invasive, US-based approach is to estimate hepatic fibrosis by assessing elasticity using an elastographic device called FibroScan (Echosens, Paris, France).[27,28] Although early reports are promising, large-scale studies with FibroScan in patients with NAFLD are currently lacking.[27,28]
Models based on clinical and or laboratory tests have also been developed as alternatives to liver biopsy for predicting NASH or fibrosis. Several of these ‘predictive fibrosis panels’ have been proposed over the past decade, including APRI (AST to platelet ratio index), the Fibrometer (platelets, prothrombin index, aspartate aminotransferase, ?2-macroglobulin, hyaluronate, urea and age), FibroTest, Simple Test (age, hyperglycemia, body mass index, platelet count, albumin and AST/ALT) and the Original European Liver Fibrosis panel (age, hyaluronic acid, amino-terminal propeptide of type III collagen and tissue inhibitor of matrix metalloproteinase). The predictive panels for fibrosis have been used predominantly in patients with chronic hepatitis C and not in NAFLD.[35-43]
Several NASH-specific biomarkers have recently been developed. The CK-18, a biomarker of apoptosis, was developed and tested in patients with NAFLD.[42] Another non-invasive biomarker (NASH Diagnostics) is a simple panel that includes Cleaved CK-18, a product of the subtraction of Cleaved CK-18 level from intact CK-18, serum adiponectin and serum resistin with an area under the curve of 90%.[43] These assays require further external validation in patients with NAFLD.[42,43]
Additionally, several groups have used high throughput genomics and proteomics techniques to investigate thousands of genes and proteins at one time, providing a molecular snapshot of the pathophysiological state of the diseased tissue. The value of this approach has been recently demonstrated by a comparison of the SELDI-based proteomics index to the serum-based FibroTest, which revealed superior predictive power of the former.[18] Nevertheless, the high cost and variability of the proteomics approach remains a substantial obstacle to the introduction of high-throughput diagnostics to clinical practice. If further validated, however, these non-invasive biomarkers for NASH or NASH-related fibrosis could be very useful in clinical practice.[44-46]
Pathgenesis
The pathogenesis of NASH appears to be a multiple-hit process. The initial insult is the development of macrovesicular steatosis with the accumulation of hepatic fat from decreased hepatic free fatty acid oxidation and/or increased hepatic de novo lipogenesis, and/or decreased lipid export from the liver. Although IR can contribute to this dysregulation of lipid metabolism, once fatty liver develops, it can worsen hepatic IR, contributing to a vicious cycle.[47-49] The second hit involves oxidative stress from mitochondrial reactive oxygen species, cytochrome P-450 enzymes, endotoxin, cytokines and environmental toxins. Regardless of its origin, oxidative stress can promote lipid peroxidation in the hepatocyte membrane, leading to the secretion of pro-inflammatory cytokines and stellate cell activation, which result in fibrosis.[47-54]
Another important pathogenic culprit is adipocytokines secreted by the white adipose tissue (WAT) related to visceral obesity. WAT is now recognized as an endocrine organ that secretes several adipokines and cytokines including adiponectin, leptin, resistin, and visfatin, TNF-?, interleukin-6 and angiotensinogen.[54] Adiponectin is an adipokine that is decreased in obesity. Furthermore, plasma adiponectin levels are decreased in NAFLD, whereas exogenous adiponectin improves hepatic steatosis in animal models of non-alcoholic fatty liver.[54] The pro-inflammatory cytokine, TNF-?, is increased in NAFLD patients and therapy directed against it can be beneficial.[52,53,55] These adipo-cytokines seem to contribute also to the pathogenesis of NASH. Although several other mechanisms, such as apoptotic pathways, may also contribute to the pathogenesis of NASH and its progression, the pathogenic details of these pathways are outside the scope of this review.
Treatment
To date, no single therapy has been approved for treating NAFLD, but a growing consensus suggests that only patients with NASH require treatment and only they should be the targets of future clinical trials. Even so, patients with other forms of liver disease may be at risk for other complications of metabolic syndrome, and treatment for the underlying components of metabolic syndrome should be addressed. Several pharmaceutical agents have been used for the treatment of NASH; however, initial management must be focused on lifestyle modification and the reversal of conditions associated with NAFLD.[56]
Initial Management - Weight Loss and Exercise (Table 1)
Lifestyle changes should include nutritional counselling with or without exercise. The pathophysiological basis for this approach is that weight reduction results in the loss of white adipose tissue, which decreases IR. Exercise can also improve muscular insulin sensitivity, which may improve the impact of IR on NAFLD. Several studies have shown that weight reduction with a calorie-restricted diet, with or without exercise, results in a significant biochemical improvement in overweight and obese adults and children. A few trials have also shown a significant reduction in ALT values in patients with biopsy proven NAFLD when they are put on calorie-restricted diets with or without exercise.[56-59]
Although lifestyle changes can lead to weight loss, the effect is usually short lived and long-term data on the histological improvement are lacking. Of some concern is the portal inflammation and fibrosis observed in morbidly obese patients undergoing rapid weight loss of more than 1.6 kg/week.[60] If weight reduction is adopted, gradual loss not exceeding 1.6 kg/week should be emphasized through the combination of dietary restrictions and regular aerobic exercise regimen including at least 30 min of exercise three to five times per week. However, the validity of this recommendation in the era of bariatric surgery has still not been established.
In addition to exercise and diet, a few studies have investigated the use of medication for weight loss. A clinical trial using Orlistat, an enteric lipase inhibitor, showed a mean decrease in body weight of 10.3 kg and significant reductions in serum transaminase levels in obese patients with NASH.[63] A 6-month pilot study of sibutramine (a serotonin and noradrenaline reuptake inhibitor that increases satiety and energy expenditure) reported weight loss, improved IR and improved biochemical and sonographic variables.[62] These findings are promising, but long-term patient tolerance to these drugs and the ability to achieve sustained weight reduction need to be addressed.
Another option for weight loss in morbidly obese patients is surgical intervention with bariatric surgery.[63-67] A recent study from the Swedish Obese Study Group suggests that bariatric surgery can be associated with improved long-term outcomes in terms of cardiovascular risk factors such as diabetes mellitus, hypertriglyceridemia and hypertension compared to a conventional weight loss group.[64] Although liver outcomes were not reported specifically, improvements in several components of metabolic syndrome are expected to have a beneficial impact on the liver disease. In fact, another study by Dixon et al. showed that NASH resolved in 82% of patients undergoing laparoscopic adjustable gastric banding (LAGB) after losing 34 ± 17 kg.[67] Patients who had metabolic syndrome showed a greater improvement in liver histology with weight loss. These and additional studies suggest a positive impact of bariatric surgery on metabolic syndrome and NAFLD.[64-67]
Treating Insulin Resistance (Table 2)
As previously noted, IR is associated with NASH or NASH-related fibrosis. Therefore, treatment strategies targeting IR is becoming increasingly popular. The insulin sensitizing agents, thiazolidinediones and metformin, are the focus of the several ongoing studies.
Thiazolidinediones improve insulin sensitivity in adipose tissue by activating the nuclear transcription factor peroxisome-proliferator activated-receptor (PPAR-gamma).[68] Improvements in IR and biochemical and histological improvements were noted in a study of 30 patients with biopsy proven NASH who were given 4 mg of rosiglitazone twice a day for 48 weeks.[69] Another study noted biochemical, histological and radiological improvements in 18 NASH patients treated with 30 mg of pioglitazone for 48 weeks.[70] Finally, in a recent clinical trial, patients with biopsy-proven NASH were randomized to a regimen containing pioglitazone (45 mg daily) and hypocaloric diet vs. hypocaloric diet alone for 6 months. This study showed biochemical and histological improvement associated with the pioglitazone arm.[71]
Despite these encouraging data, two important drawbacks of these agents are weight gain and the temporary nature of the improvements. For both agents, nearly two-thirds of the patients gained weight and improvements in biochemical abnormalities were reversed after treatment was discontinued. Several smaller clinical trials have reported similar findings. Well-powered, randomized, placebo-controlled trials are needed to assess the efficacy and safety of these drugs.
In addition to thiazolidinediones, several small clinical trials have reported the potential efficacy of metformin in treating NASH.[72,73] Metformin is a biguanide that improves IR and hyperinsulinemia by decreasing hepatic glucose production, increasing peripheral glucose uptake by muscles and reversing TNF-?-induced IR.[72] Small trials using metformin have reported improvement of amintransferases.[73,74] A pilot study of metformin reported initial improvements in ALT, but no difference after 12 months of therapy.[74] A large open-label study of nondiabetic NAFLD, randomized patients to metformin 2 g daily, diet, or 800 IU vitamin E/day.[75] A significantly greater number of subjects taking metformin normalized ALT levels compared with the diet or vitamin E groups. Moreover, these subjects showed significant improvements in steatosis, inflammation and fibrosis compared to their baseline, but no histological follow-up was available for the control arm.
Although metformin was well tolerated and biochemical improvement was shown, histological data remain very limited. Well-controlled trials are needed to assess the efficacy and safety of metformin in patients with NAFLD.
A number of new agents targeting IR have been used in patients with NAFLD. A small pilot study of patients with NASH used an insulin-type fructan, oligofructose, showing a decrease in serum levels of ALT and AST.[76] Nateglinide, an insulin secretagogue, was used in five diabetic patients with NASH for 20 weeks and showed improved biochemical and histological parameters compared to the control group.[77] Muraglitizar, a dual PPAR-alpha and -gamma agonist, and Rimonabant, a selective cannabinoid-1 receptor blocker, have shown promising results in obese and diabetic patients with metabolic syndrome, but these studies lack liver-related outcome data.[78,79]
Lipid-Lowering Medications
Hypertriglyceridemia and low HDL are components of metabolic syndrome and its associated NAFLD. Therefore, several investigators have attempted to explore the potential role of lipid-lowering agents in treating patients with NAFLD. A clinical trial using Gemfibrozil, a fibric acid with lipid-lowering activity, showed some biochemical improvements in patients with NAFLD when given at the dose of 600 mg for 4 weeks.[80] On the contrary, clofibrate produced no biochemical or histological improvements.[81]
Small pilot trials using HMG-CoA reductase inhibitors (statins) have shown significant reductions in serum ALT levels.[82,83] A small pilot study using pravastatin at 20 mg for 6 months normalized liver enzymes and improved hepatic inflammation in patients with NASH.[84] A pilot study using atorvastatin improved serum aminotransferase levels as well as lipid levels in patients with NAFLD and showed that atorvastatin was both effective and safe.[85]
An important issue regarding the use of statins in patients with NAFLD is their potential heptotoxicity. However, increasing evidence suggests that the use of standard doses of these drugs in patients with elevated liver enzymes is not associated with a significantly increased risk of serious hepatotoxicity.[86]
Antioxidants (Table 3 and Table 4)
Given the potential role of oxidative stress in the pathogenesis of NASH, investigators have focused on the use of antioxidants for the treatment of NAFLD to protect cellular structures against damage from oxygen free radicals and from reactive products of lipid peroxidation. Two small pilot trials showed improved liver enzymes with vitamin E treatment.[87,88] But subsequently, two small, randomized, controlled trials failed to show any benefit.[89,90] A randomized study comparing vitamin E (1000 IU/day) and vitamin C (1000 mg/day) to placebo for 6 months showed no differences in ALT or hepatic inflammation at the end of the study.[91]
Other potential anti-oxidant therapies for NASH include betaine and N-acetylcysteine.[92,93] Betaine is a naturally occurring metabolite of choline that increases S-adenosylmethionine levels. A small, uncontrolled pilot study of 10 patients with NASH treated with betaine for 1 year, showed improvements in serum AST and ALT levels as well as grades of steatosis, necroinflammation and the stage of fibrosis.[56]
Given the role of TNF-? in inducing both necroinflammation and IR, anti-TNF agents have been considered in the treatment of NASH. Pentoxifylline, a TNF-? inhibitor, has been used in patients with NASH. Two pilot studies evaluating the role of pentoxyfylline in NASH reported significant improvements in AST and ALT as well as potential improvement in IR.[53,55]
Ursodeoxycholic Acid
The initial open-label studies of ursodeoxycholic acid (UDCA), a potential cytoprotective agent, in NAFLD generated considerable enthusiasm.[81] However, no benefit was observed in a relatively large, well-designed randomized, double-blind, placebo-controlled trial involving 166 NASH patients who were randomized to UDCA 13-15 mg/kg/day or placebo for about 1 year. Although UDCA was safe and well tolerated, it was not significantly different in terms of liver biochemistries or histology when compared with placebo.[94]
Other Agents (Table 4)
Suppressing the renin-angiotensin system with angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARB) produces metabolic effects that could prevent type-2 diabetes mellitus in hypertensive patients or those with congestive heart failure. The ARBs, telmisartan and irbesartan, activate PPAR-gamma and decrease IR.[95-97] A preliminary study of patients with hypertension and NASH treated with an ACEI has reported some histological improvement.[98]
In addition to ACEI or ARB, folic acid has been used for treatment of NASH. An open-label pilot study in 10 patients with biopsy proven NASH used 1 mg/day of folic acid for 6 months and found no significant biochemical improvement after 6 months of therapy.[99]
Furthermore, treatment of bacterial overgrowth may also have a role in NAFLD patients. Several studies have suggested that intestinal bacterial overgrowth plays a role in the pathogenesis of NASH. Bacterial endotoxins can stimulate hepatic inflammatory cytokine production and increase oxidative stress leading to subsequent liver injury. A recent study involving 22 NAFLD patients using probiotic VSL#3 showed improvement in ALT levels as well as other markers of lipid peroxidation.[100,101]
Despite these large numbers of pharmacologic agents that have been used to treat NASH, most of the studies are of small size and of short duration. Therefore, one can conclude that in 2008, there is no established treatment for patients with NASH. Nevertheless, the future clinical trials for NASH, targeting specific pathogenic pathways with the appropriate sample size and duration are urgently needed.
In summary, NAFLD is among the most common causes of chronic liver disease worldwide, and can potentially progress to cirrhosis, liver failure and hepatocellular carcinoma. NAFLD has the potential for major economic impact on healthcare costs because of liver-related morbidity and mortality. Investigations over the last two decades have led to a better understanding of the natural history, epidemiology and pathophysiology of this disease. However, despite having tested a large number of agents, no single agent or combination of agents stands out as a therapy with proven efficacy. Effective preventive and therapeutic strategies still need to be developed to tackle this evolving global epidemic of NAFLD. A multidisciplinary approach using lifestyle modifications and optimizing metabolic risk factors is the best option for now, until the results of the ongoing randomized, double-blind, placebo-controlled trials investigating multiple therapeutic options become available.
http://www.medscape.com/viewarticle/578709_1
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