Review Article: Current Management of Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

Z. M. Younossi


Aliment Pharmacol Ther. 2008;28(1):2-12. 

In This Article


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]

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.[56,57,58,59]

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.[63,64,65,66,67] 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.[64,65,66,67]

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-α-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]

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]

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-α in inducing both necroinflammation and IR, anti-TNF agents have been considered in the treatment of NASH. Pentoxifylline, a TNF-α 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]

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]

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.[95,96,97] 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.

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