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DOI: 10.1055/s-0028-1091984
Current and Emerging Therapies in Nonalcoholic Fatty Liver Disease
Stephen A HarrisonM.D.
Chief of Hepatology, Brooke Army Medical Center
3841 Roger Brooke Drive, Ft. Sam Houston, TX 78234
Email: Stephen.harrison@amedd.army.mil
Publication History
Publication Date:
27 October 2008 (online)
ABSTRACT
The prevalence of obesity and the metabolic syndrome (MS) is on the rise, and subsequently the hepatic manifestation of MS, nonalcoholic fatty liver disease (NAFLD), has become a common entity in clinical practice. Most patients with NAFLD face medical complications related to their underlying MS in other organ systems; however, a small but significant group of patients with the more aggressive form of fatty liver, nonalcoholic steatohepatitis (NASH), are at risk of developing cirrhosis and hepatocellular carcinoma. As patients are generally asymptomatic, often their disease goes unrecognized. This is particularly true for NASH, where liver biopsy is currently required to make the diagnosis. Once diagnosed, no one treatment has been shown to be universally efficacious and those that are of benefit are not without side effects. Effective treatment regimens directed at both decreasing insulin resistance as well as the processes leading to necroinflammation and hepatic fibrosis have been investigated and include lifestyle modification, surgical therapies, and pharmacotherapy. This review focuses on current and potential future therapies for NASH.
KEYWORDS
Fatty liver - nonalcoholic steatohepatitis (NASH) - nonalcoholic fatty liver disease (NAFLD) - metabolic syndrome - thiazolidinediones (TZDs)
Zelman first described the existence of liver disease in very obese men in 1952.[1] Subsequently, in 1958 Westwater and Fainer confirmed the presence of abnormal liver function tests and liver morphology in obese patients, and also showed that these parameters improved with weight loss.[2] It was not until 1980, however, that the term nonalcoholic steatohepatitis (NASH) was coined by Ludwig and colleagues, who first described the pathological changes still used today.[3] Rapidly increasing in prevalence in the United States, as well as throughout Western Europe and parts of Asia, nonalcoholic fatty liver disease (NAFLD) is currently widely accepted as a spectrum ranging from isolated fatty liver to NASH. Although isolated fatty liver is thought to have a generally benign histopathological course, recent data suggest a link with increased risk of cardiovascular disease.[4] [5] [6] Furthermore, it appears that NASH may progress to cirrhosis at a rate of ~10% over a 20-year period.[7] Given this data, therapies aimed at improving NAFLD are urgently needed. This review will focus on current and emerging therapies for this disease.
#PATHOGENESIS
Our understanding of the development of NAFLD is evolving. The initial “2 hit” hypothesis was predicated on the development of steatosis as the so-called “first hit” as a result of insulin and likely leptin resistance, leading to enhanced free fatty acid flux to the liver, upregulated hepatic de novo lipogenesis, increased free fatty acid oxidation, and decreased export of hepatic triglycerides in the form of very low-density lipoprotein.[8] Progression to steatohepatitis was thought to require a “second hit,” involving oxidative stress which promoted lipid peroxidation and production of proinflammatory cytokines, leading to subsequent inflammation and fibrosis.
However, this concept of 2 distinct hits has been debated recently given our current understanding of the potentially deleterious effects of peripheral and hepatic insulin resistance. Clearly, the pathogenetic processes that lead to steatosis and/or steatohepatitis are multifactorial and influenced by both environmental and genetic factors. Although the specific pathways leading to inflammation and fibrosis are not clearly delineated, evidence supports a role for dysregulated lipid partitioning mediated by insulin resistance and concomitant altered cytokine profiles.[9] Oxidative stress is thought to be obligatory, and along with lysosomal cathepsin release, mitochondrial dysfunction, and endoplasmic reticulum stress, cellular apoptosis and further inflammation ensue and activation of hepatic stellate cells with collagen deposition within the hepatic sinusoids becomes apparent. Furthermore, the ability of the liver to repair and recover from injury appears variable and may impact the rate of progression as well as the severity of liver disease.[10]
#THERAPEUTIC MODALITIES
Progress in developing potential therapies for NAFLD has been made in recent years and is founded on improvement in underlying peripheral and hepatic insulin resistance. Dietary change, exercise, weight loss, and pharmacotherapy may all improve insulin resistance and are thus targets for therapeutic trials (Fig. [1]). Additionally, agents that reduce oxidative stress and/or apoptosis or have cytoprotective properties have been evaluated, albeit typically in small uncontrolled trials. Furthermore, the treatment of specific underlying components of the metabolic syndrome (MS) such as hypertension, diabetes mellitus, or dyslipidemia has been suggested.
Figure 1 Insulin resistance and treatment targets in nonalcoholic steatohepatitis.
Lifestyle Modifications
In the United States and in select parts of the world, obesity and subsequent insulin resistance are reaching epidemic proportions with nearly 1.7 billion at risk for weight-related disease and an estimated overall prevalence of insulin resistance in the general population that is now thought to be around 45%.[11] [12] [13] [14] Reasons for this dramatic increase in obesity and insulin are multifactorial and include the increased consumption of high-fructose corn syrup (HFCS), processed carbohydrates, and saturated fatty acids along with decreased milk and mono- and polyunsaturated fatty acid consumption.[15] [16] [17] Dietary intervention and exercise, though lacking appeal and often limited by patient compliance, remain first-line therapy for this disease. Diet-induced weight loss is associated with physiologic changes that result in improved insulin sensitivity, reduced adipose tissue inflammation and reduced hepatic free fatty acid supply. Surprisingly, appropriately powered, prospective, randomized controlled trials of dietary intervention and weight loss in patients with NASH are lacking, although it is believed that even a modest degree of gradual weight loss of 10% body weight will result in improvement of transaminases, hepatic steatosis, inflammation, and fibrosis.[9] [18] [19] [20] [21] Preliminary studies support this notion with two studies showing improved serum aminotransferases with weight loss although only one of these studies had histologic follow-up (albeit incomplete with 14 of 31 patients undergoing repeat liver biopsy).[19] [22] Larger trials with appropriate histologic follow-up are mandatory to confirm the general beneficial effects of this simple, yet difficult to implement, therapy of dietary and lifestyle modification.
#Pharmacotherapy
As lifestyle changes are difficult to sustain long-term, other modalities such as pharmacotherapeutic or surgical approaches have been investigated in the treatment of NASH. Using the simplified 2-hit hypothesis, various targets for potential pharmacotherapy have been identified. These include therapies directed at improving insulin resistance, reducing oxidative stress, decreasing hepatic fibrosis, improving the underlying metabolic syndrome, or promoting weight loss. Surgical approaches also directed at weight loss have been investigated.
#Metformin
Metformin, commonly used to treat diabetes mellitus, improves blood glucose levels by decreasing hepatic glucose production and increasing glucose utilization in peripheral skeletal muscle.[23] Metformin in the treatment of NAFLD has produced mixed and generally disappointing results. Lin et al studied a population of ob/ob C57BL-6 mice, who are genetically deficient in leptin.[24] As a result, of their lack of this appetite-suppressing gene, ob/ob mice are prone to insulin resistance, hyperinsulinemia, and fatty liver. Hepatic steatosis decreased, hepatomegaly was reduced, and aminotransferases were improved significantly in ob/ob mice treated with metformin.
Marchesini et al[25] treated 20 biopsy-proven NASH patients with metformin 500 mg 3 times per day for 4 months. Significant improvements were seen in insulin resistance and aminotransferase levels, with 50% of subjects normalizing their transaminases. Liver volume, as measured by ultrasound, decreased by 20%. Subsequently, Bugianesi et al[4] followed 110 nondiabetic patients with NAFLD over a 12-month period: 55 were treated with metformin 2000 mg daily, 28 with vitamin E, and 27 with a prescribed diet. Aminotransferases improved in association with weight loss in all groups with metformin-treated patients showing the most biochemical improvement in multivariate analysis. Posttreatment liver biopsy performed on 17 of the metformin-treated group showed statistically significant changes in liver fat, necroinflammation and fibrosis. Although this was promising, any positive findings were tempered by the incomplete histologic follow-up of patients.
A more recent Turkish study of 36 biopsy-proven NASH patients treated with metformin 850 mg twice per day plus a calorie-restricted diet versus diet alone for 6 months showed no significant differences in necroinflammatory activity or fibrosis between the two groups on repeat biopsy.[26] This was supported by an earlier study of 15 patients treated with metformin (20 mg/kg/day in three divided doses) for 48 weeks, which despite initial improvement in serum aminotransferase levels, a return to pretreatment values after 3 months was observed.[27] Ten patients from this study population had a posttreatment biopsy with only minimal improvement in necroinflammation and fibrosis. Based on the currently available data, it seems reasonable to conclude that metformin is not an ideal monotherapy agent for the treatment of NASH. Prospective, randomized, controlled trials with metformin are needed to definitively assess the true efficacy of this drug for the treatment of NASH.
#Thiazolidinediones
The thiazolidinediones (TZDs) are another class of diabetic medications that have been extensively studied in the treatment of NASH. These medications include pioglitazone and rosiglitazone, which act as peroxisomal proliferator activated receptor-γ (PPAR-γ) agonists leading to increased fatty acid oxidation and decreased fatty acid synthesis within hepatocytes. The resultant improved insulin sensitivity in both hepatocytes and skeletal muscle is one mechanism of action that may explain TZDs usefulness in NASH patient populations.[28] [29] Initial studies such as that by Neuschwander-Tetri et al treated 22 patients with rosiglitazone for 48 weeks and showed both improvement in insulin sensitivity and hepatic histology.[29] Limitations of this early work include the lack of a control group and a return to baseline of serum aminotransferases 6 months after discontinuation of therapy.
Subsequent randomized placebo controlled studies have supported the beneficial effects of TZDs on insulin sensitivity, serum aminotransferases, and hepatic histology (Table [1]). Belfort et al demonstrated significant improvement in these parameters in patients treated with low-calorie diet plus pioglitazone versus low calorie diet plus placebo (n = 55) for 6 months.[30] Hepatic fibrosis was not significantly improved in this trial, which was limited by its relatively short duration of therapy. Aithal et al followed 78 NASH patients treated with either placebo or pioglitazone for 48 weeks and abstract data demonstrated significant improvement in all parameters of hepatic histology.[31] Fibrosis was notably improved in the treatment group when compared with both the initial liver biopsy as well as the follow-up placebo liver biopsy.
| Study | N | Medication/Study Design | Time | AST/ALT | Steatosis | Necro-inflammation | Hepatic Fibrosis | Comment |
| Neuschwander-Tetri et al[29] | 30 | Rosiglitazone open label | 48 wk | ↓ | ↓ | ↓ | No change | No placebo, 5/25 dropped out |
| Promra et al[78] | 18 | Pioglitazone open label | 48 wk | ↓ | ↓ | ↓ | ↓ | No placebo |
| Sanyal et al[79] | 20 | Pioglitazone/Vit E vs. Vit E | 6 mo | ↓ | ↓ | ↓ | ↓ | 2/10 patients in pioglitazone group stopped therapy |
| Belfort et al[30] | 55 | Pioglitazone vs. placebo | 6 mo | ↓ | ↓ | ↓ | No change | 2.5 kg wt gain in tx group |
| Lutchmanet al[80] | 21 (9) | Pioglitazone | 48 wk | ↓ | ↓ | ↓ | ↓ | 9 patients followed 48 wk off meds → benefits not maintained |
| Idilman et al[81] | 74 | Rosiglitazone vs. Metformin vs. diet/exercise | 48 wk | ↓ | ↓ | ↓ | No change | Only 29 patients with sequential biopsies |
| Aithal et al[31] | 78 | Pioglitazone vs. placebo | 1 y | ↓ | ↓ | ↓ | ↓ | Abstract only |
| Ratziu et al[33] | 63 | Rosiglitazone vs. placebo | 48 wk | ↓ | ↓ | No change | No change | Low-grade baseline disease (NAS 4) |
| ALT, alanine aminotransferase; AST, aspartate aminotransferase; NAS, NAFLD activity score. | ||||||||
Another recent study comparing 75 patients with NASH treated for 48 weeks with either metformin, rosiglitazone, or isolated dietary/exercise counseling provided support for the metabolic and histologic benefits to the TZDs.[32] Interestingly, the biochemical benefits seen with therapy persisted 6 months after discontinuation of insulin sensitizing medication, although this study can be criticized for inadequate follow-up histology, with 40% of patients refusing a second liver biopsy.
These promising results from several TZD treatment trials in NASH were called into question by the recently published FLIRT trial, which followed 63 patients with NASH treated for one year with either rosiglitazone or placebo.[33] Although the patients receiving rosiglitazone did show a statistically significant improvement in serum aminotransferases, insulin sensitivity, and hepatic steatosis, they did not show an improvement in other histologic parameters, notably the NAFLD Activity Score (NAS) score or overall fibrosis. Although these results are intriguing and certainly provide evidence for a subpopulation of NASH patients that do not appear to respond to therapy with the TZDs, this study is limited by the markedly low NAS score at baseline (4), which leaves little room for improvement and suggests borderline NASH initially. Certainly further study would be beneficial to better elucidate if TZD therapy is both effective and sustainable.
The side effects profile of the TZDs also requires further mention as it may substantially limit the widespread use of these medications (at least as monotherapy). Weight gain has been universally noted, usually on the order of 2 to 5 kg, and this increase does not always return to baseline on medication discontinuation. In addition, lower extremity edema is seen in up to 5% of patients chronically taking a TZD. These medications are contraindicated in congestive heart failure and the recent controversy over a possible increase in adverse cardiac events in diabetic men chronically taking rosiglitazone (Avandia®, GlaxoSmithKline, Mississauga, Ontario, Canada) (seen in a retrospective meta-analysis) has prompted ongoing prospective studies, which will hopefully definitely resolve this troublesome issue.[34] One final side effect that should be considered is an apparent increase in osteoporosis seen in long-term therapy with the TZDs in postmenopausal women.[35] Although not an absolute contraindication to therapy in most patients, it warrants consideration and discussion with patients prior to chronic use of this class of medications.
The TZDs are likely the most studied class of insulin sensitizing medications in the treatment of NASH and have certainly shown the most promise. Although clearly not a treatment panacea, they represent an option for patients as an initial step along with diet and exercise to improve insulin sensitivity, and hopefully hepatic histology.
#Incretin Analogs
Another newer class of medications, glucagon-like protein-1-receptor agonists, that has been shown to be a useful adjunct in the treatment of diabetes mellitus may also be beneficial in the treatment of NASH. This class of medications acts as an incretin analog in the body and promotes insulin secretion while suppressing inappropriate glucagon secretion, slowing gastric emptying, and increasing satiety. Although these mechanisms work to promote modest weight loss, nausea is a common side effect that can limit the dosing of this injectable medication.[36] Preliminary studies in animal models with fatty liver and case reports in humans have shown promising results with improved serum aminotransferases and decreased hepatic steatosis, but further study with well-designed human trials is required.[37] [38] [39]
#Statins
The significant role that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors, also known as statins, have played in decreasing mortality among patients with diabetes mellitus and cardiovascular disease is irrefutable.[40] Their role in patients with abnormal liver function tests and/or chronic liver disease has been less clear. First, there has been much concern for worsening hepatic function and or enzymes with statin use. Hepatic injuries associated with statins include (1) asymptomatic elevations in aminotransferases (common), (2) clinically significant acute liver injury (very rare), (3) fulminant hepatic failure (profoundly rare).[41] No association has been found, clinically or histologically, between asymptomatic elevations in aminotransferases, without concurrent rise in bilirubin, and acute or chronic hepatic injury.[42] In the majority of cases, these elevations do not progress and sometimes return to baseline, despite continued statin use.[43] Clinically significant liver injury usually occurs when statins are used in conjunction with other medications, including ezetimibe.[41] [42] [44]
When considering the use of statins in NAFLD patients, it is important to note that there are normal fluctuations in aminotransferase levels in patients with and without chronic liver disease[40] [42] In a recent multicenter, randomized, double-blind study, 326 subjects with hyperlipidemia and well-compensated chronic liver disease, including NAFLD and chronic hepatitis C, were treated with high-dose pravastatin or placebo for 36 weeks. No statistically significant changes in serum ALT levels were observed in patients treated with pravastatin or placebo.[43] In addition, studies have shown that patients with elevated liver enzymes at baseline due to NAFLD are not at increased risk of hepatotoxicity when compared with patients with normal liver enzymes at baseline.[42] [45]
Although clearly statins appear safe for the treatment of hyperlipidemia in NAFLD patients, the issue of whether or not they are efficacious in the treatment of NASH is more uncertain. A pilot study compared before and after liver biopsy results in 4 NASH patients treated with Pravastatin for 6 months.[46] Three patients had improvement in grade of inflammation, while one had improvement in degree of steatosis.
In a recent Swedish study, 68 patients with NAFLD who had not previously been on statins were rebiopsied 10 to 16 years after baseline biopsy.[40] This study showed that despite initial higher Body Mass Indexes and rates of diabetes, those patients receiving statins had a significant reduction in hepatic steatosis when compared with those who did not, with an overall low rate of fibrosis progression. These early studies suggest some benefit to statin therapy in this patient population, although larger placebo controlled studies are needed to substantiate these results.
#Cytoprotective Medications and Antioxidants
Although medications directed at decreasing insulin resistance and improving metabolic parameters seem the most suited to therapy of NASH, medications that are classified as hepatoprotective agents or antioxidants have also been studied. These medications are thought to reduce oxidative stress and decrease hepatic inflammation, and if shown to be of benefit in NASH, would be easy to use in clinical practice.
Derived from mammals, ursodeoxycholic acid (UDCA) is a naturally occurring bile acid, with an excellent safety profile, that is used in various liver diseases to include primary biliary cirrhosis and primary sclerosing cholangitis. Shown to have hepatoprotective properties, including membrane-stabilizing and cytoprotective effects, UDCA may improve not only hepatic biochemistry, but also hepatic histology in patients with cholestatic liver disease.[47] [48] [49] In an early pilot study comparing UDCA to clofibrate in biopsy-proven NASH patients, the UDCA group showed a significant improvement in serum alanine aminotransferase (ALT) levels and histological grade of steatosis compared with clofibrate-treated patients.[49] Similarly, 8 of 12 patients with biopsy-proven NASH treated with UDCA for 6 months normalized their aminotransferases, although no histologic follow-up was obtained.[50]
These promising initial results were not substantiated by a large multicenter trial with 107 NASH patients treated with UDCA or placebo for 2 years.[47] Although there was a significant histological improvement in the posttreatment biopsies of the UDCA group, comparable findings were present in the placebo group, with overall 40% reduction in steatosis and 21% reduction in fibrosis. This study highlights the need for large placebo controlled studies to confirm that improvement in histopathology extend beyond the normal natural history of NASH where a sizable proportion of patients show spontaneous histologic improvement.
Although this has dampened enthusiasm for UDCA as monotherapy, there may be a role for UDCA in combination with other treatments. One case report of a patient with psoriasis, diabetes, and NASH showed treatment with UDCA and pioglitazone improved serum transaminases as well as hepatic steatosis and fibrosis on repeat liver biopsy.[48] The role of UDCA as an adjunctive type of therapy remains to be further evaluated.
Antioxidants intuitively are intriguing has a potential therapy. Pathophysiologically, oxidative stress appears to be a part of mitochondrial and endoplasmic reticulum stress. As such vitamin E has been evaluated as a possible treatment for NASH. Two relatively small studies have evaluated vitamin E in children with obesity-related serum aminotransferase elevation (NAFLD) and echogenic liver on ultrasonography and found conflicting results.[51] [52] Lavine et al[52] found that daily vitamin E for a mean of 5.2 months normalized serum aminotransferase and alkaline phosphatase levels. On the other hand, Vajro et al showed no difference in posttreatment transaminases or echogenicity on ultrasound when comparing patients treated with diet plus vitamins E versus diet plus placebo for 5 months.[51]
In the adult population, 16 biopsy-proven NASH patients were treated with lifestyle modification (diet and exercise) with or without vitamin E for a period of 12 weeks.[53] Vitamin E supplementation provided no statistically significant improvement in serum aminotransferase levels. A larger randomized, placebo-controlled study of 45 NASH patients added vitamin C to vitamin E in an effort to improve antioxidant effects.[54] Although serum aminotransferases and necroinflammation were not improved after 6 months of therapy, repeat biopsies did reveal significant improvement in fibrosis scores between the two groups. This study suggests there may be a role for vitamin E therapy in the future, but certainly further multicenter randomized controlled trials would be of benefit.
Betaine is another medication which increases levels of S-adenosyl-L-methionine (SAM), a known essential player in cellular membrane integrity and hepatoprotection, and has been investigated in the treatment of NASH.[55] [56] [57] In an animal model of alcoholic liver disease, subjects given betaine-enriched diets had a 4-fold increase in SAM levels and were protected against the expected fatty infiltration that usually results from ethanol ingestion.[55] One year of treatment with betaine in 10 NASH patients significantly improved serum transaminases as well as hepatic steatosis, inflammation, and fibrosis.[56] As it was generally safe and well tolerated, betaine warrants further investigation with larger placebo controlled trials in the treatment of NAFLD and NASH.
Overall, antioxidant therapy has been disappointing as a potential therapeutic target. One potential explanation is that current antioxidant therapies are unable to effectively penetrate the inner mitochondrial membrane and impact reactive oxygen species development. Formulations that increase delivery of antioxidant intracellularly may improve their usefulness in clinical practice.
#Weight Loss Promotion
Although medications to improve insulin sensitivity, reduce oxidative stress, and decrease fibrosis all show some promise in the treatment of NASH, ultimately sustained weight loss may produce the best results as it improves all these parameters. In addition to the lifestyle modifications previously mentioned, there are several medications as well as surgical interventions that have been evaluated as potential treatments.
#Orlistat
Orlistat has been the most studied weight loss medication as a potential treatment for NASH. This medication inhibits gastric and pancreatic lipase, which is needed to break down triglycerides into free fatty acids and has been shown to prevent 30% of dietary triglycerides from being absorbed. Pilot studies with orlistat given for 6 months along with dietary counseling showed promising improvement in serum aminotransferases as well as hepatic steatosis and inflammation.[58]
Two subsequent randomized placebo controlled trials treated patients for between 6 to 9 months with significant improvement in hepatic steatosis seen in both orlistat groups.[59] [60] However, further benefits in hepatic histology (via improvement in necroinflammation) or serum aminotransferases were only seen in those patients who sustained 9% weight reduction, regardless of whether receiving placebo or orlistat. Patients in both trials lost an average of 6 to 8% of their body weight; however, it is important to note that there was not a significant difference in weight loss between placebo and orlistat groups. Therefore, it would appear that orlistat is effective treatment for NASH only in the setting of significant weight loss, and as an only modestly successful weight loss agent, it falls shorts as a treatment panacea for NASH.
#Rimonabant
The endocannabinoid (EC) system is involved in the regulation of food intake and body weight. In the setting of obesity, the EC system appears to be upregulated and as such, represents a novel target for medical therapy of NASH. The EC system encompasses a network of receptors and their ligands as well as the enzymes that synthesize and degrade these ligands.[11] The cannabinoid type I (CB1) receptors are found throughout the body and their activation leads to increased hepatic lipogenesis, fatty acid synthesis in adipocytes, and decreased adiponectin.
Rimonabant is a selective CB1 receptor antagonist that has been shown to decrease hepatic lipogenesis and increase satiety, adiponectin levels, and glucose uptake, thereby improving insulin levels and lipid profiles.[61] [62] This agent was initially developed as a weight loss medication and has been well studied in two large randomized placebo controlled multicenter trials. The Rimonabant in Overweight/Obesity (RIO) trial based in Europe (RIO-Europe) and North America (Rio-North America) trial followed 1507 and 3040 patients, respectively, for 2 years, with an average weight loss of ~6 kg in patients receiving rimonabant versus 1 to 2 kg in the placebo groups.[63] [64] The metabolic improvement of the patients receiving rimonabant was notable, with significant improvements in lipids profiles to include decreased low-density lipids and triglycerides, and improved insulin sensitivity with the resolution of metabolic syndrome in one-third of patients. Two other large studies compared rimonabant to placebo in patients with hyperlipidemia (RIO-Lipids)[65] and diabetes (RIO-Diabetes)[66] with a 3 to 6 kg weight loss after 1 year of therapy, but perhaps more notably, significant improvements in lipid profiles, glycosylated hemoglobin (HgA1C), adiponectin, and C-reactive protein were seen. These metabolic benefits appear to exceed what could be attributed directly to the weight loss and do suggest direct effects of this medication, which may have application in the treatment of NASH.
Preliminary animal studies along with isolated case reports do suggest a benefit with rimonabant therapy in the setting of NASH.[61] Two large multicenter, randomized, placebo controlled trials (one in diabetic patients and one in nondiabetic patients) are currently underway to better assess any role this medication may have in the medical therapy of NASH. One potential side effect that requires further evaluation is an association with psychiatric problems to include depression with rimonabant. This has been predominantly in patients with a history of significant psychiatric illness and appropriate screening algorithms are being developed that will hopefully limit this otherwise promising drug's use in high-risk patient populations.
#Surgical Interventions
Due to the overwhelming burden of obesity and its inherent metabolic consequences, as well as the difficulty in achieving weight loss via lifestyle modification, the number and quality of bariatric surgery procedures performed has risen dramatically. Enthusiasm for bariatric surgery as a potential treatment for NAFLD was initially dampened due to evidence that NAFLD worsened in the setting of jejunoileal bypass surgery. A subsequent study by Kral et al[67] using biliopancreatic diversion showed improvement in steatosis, but variable change in fibrosis with some patients showing fibrosis progression and others with fibrosis regression. These initial disappointing results changed with the evolution of bariatric surgery beginning in 2004 to include the Roux-en-Y gastric bypass operation and laparoscopic adjustable band gastroplasty. Numerous studies using these techniques have demonstrated significant improvement in steatosis, hepatocellular injury, and fibrosis (Table [2]).[68] [69] [70] [71] [72] [73] [74] [75] [76] [77] In fact, complete resolution of NASH in as many as 75 to 100% of cases has been described in some series.[68] [69] [72] [73] [74] [75] [76] [77] However, not all results are so positive, and collective evidence suggests that a small minority of bariatric surgery patients may develop either worsening steatohepatitis[82] or mild fibrosis.[69] The impact of bariatric surgery across the entire spectrum of NAFLD is further reviewed elsewhere in this issue of Seminars.[83] Long-term studies assessing the natural history of this fibrosis development are needed and at the present time, the clinical significance of this minor fibrosis development is uncertain. However, there is clear evidence for significant improvement overall with respect to NASH and careful thought should be given to consideration of bariatric surgery in the morbidly obese patient whose cumulative health problems would warrant this invasive procedure.
| Study | Year | N | Type of Surgery | Mean Age | Mean BMI | Mean Follow-Up Interval | Mean Change in Weight/BMI | % Change in Weight/BMI | Steatosis Improvement | Pericellular Fibrosis Change | Hepatocellular Injury Improvement | NASH Resolution | Histopathologic Worsening |
| Dixon et al[68] | 2004 | 36 | LAGB | 43 (10.3) | 47 (10.6) | 25.6 mo | 34 kg | 52% | Significant (p < 0.001) | 91% improvement; 70% complete resolution | 100% | 82% | None |
| de Almeida et al[73] | 2006 | 16 | RYGBP | 40.2 (9.5) | 53.4 (8.8) | 23.5 mo | 22.3 kg | 42% | 75% complete resolution | 50% improvement | 69% complete resolution | 94% | None |
| Barker et al[72] | 2006 | 19 | RYGBP | 48.6 | 47 (4.4) | 21.4 mo | 18 kg | 52.4% | 100% | 47% improvement | Significant improvement (p < 0.001) | 89% | 10.5% had mild fibrosis increase |
| Mattar et al[71] | 2005 | 70 | RYGBP (41) | 49 (9) | 56 (11) | 15 mo | 46.8 kg | 59% | 37% complete resolution | 20% complete fibrosis resolution | NA | NA | None |
| LSG (23) | |||||||||||||
| LAGB (6) | |||||||||||||
| Mathurin et al[69] | 2006 | 185 (121) | BIB, LAGB | 40.6 | 47.1 | 12 mo | 27 kg | 19% | Significant (p < 0.0001) | 0.14 to 0.38 (p = 0.0001) | NA | 75% | Mild fibrosis increase at 1 year |
| Mottin et al[75] | 2005 | 90 | RYGBP (majority) | 35.6 (1.1) | 46.7 (0.88) | 12 mo | NA | 81.4% | 82.2% (54% complete resolution) | NA | NA | NA | None |
| Clark et al[74] | 2005 | 16 | RYGBP | 43.9 (8.1) | 51.1 (6.1) | 305 d | 53.7 kg | 35.4% | 81% complete resolution | 43% | 86% | 81% | None |
| Furuya et al[70] | 2007 | 18 | RYGBP | 46.6 (7.3) | 51.7 (7.4) | 24 mo | 19.3 kg | 38% | 89% (84% complete resolution) | 75% of cases resolved fibrosis | 50% | No patients with NAS of > 4 | None |
| Liu X et al[76] | 2007 | 39 | RYGBP | 41.4 (9) | 47.7 (6.2) | 18 mo | 50.2 kg | 38.2% BMI | 97% resolved macrosteatosis | Centrilobular fibrosis improvement: 50% → 25% | 100% | 100% | 2.5% developed mild portal fibrosis |
| Kral et al[67] | 2004 | 104 | BPD | 36.9 (9) | 47 (8.4) | 41 mo | 38 kg | 34% | Decreased from grade 1.57 to 0.52 (p < 0.0001) | Severe fibrosis improvement in 27% of patients; 40% developed mild fibrosis | NA | NA | Mild fibrosis increase over > 3 years |
| Csendes et al[77] | 2006 | 16 | RYGBP | 46.2 | 44.3 | 17.5 mo | 15.7 kg | 35% | 93% | 4/5 (80%) | 5/5 (100%) | 100% (5 pts) | 6.7% (mild pericellular fibrosis) |
| BIB, biliointestinal bypass; BPD, biliary pancreatic diversion; BMI, body mass index; LAGB, laparoscopic adjustable band; LSG, laparoscopic sleeve gastrectomy; NAS, NAFLD activity score; NASH, nonalcoholic steatohepatitis; RYGBP, Roux-en-Y gastric bypass. | |||||||||||||
CONCLUSION
The global epidemic of obesity as a result of sedentary lifestyles, increased processed carbohydrates and HFCS intake has led to a dramatic increase in the prevalence of the generally asymptomatic NAFLD. In the subset of these patients with NASH, accumulation of fat in hepatocytes with subsequent oxidative stress and inflammation can lead to fibrosis, which may ultimately progress to cirrhosis or promote the development of HCC. Treatment strategies ranging from simple lifestyle modifications to pharmacologic agents and even invasive surgical procedures have been investigated as potential treatments for this chronic liver disease. These regimens target different steps in an intertwined and interdependent pathway that is far more complicated than the 2 hit hypothesis (Fig. [1]) would suggest. These modalities have shown varying degrees of promise and are not without side effects, cost, or risks. At the present time, it is regrettable there is no one ideal therapy suitable for all patients. Future trials are required that may combine therapies in an effort to maximize histologic benefit, while minimizing side effect profile. For the multitude of patients currently affected with this chronic liver disease, clinical trials or a multidisciplinary approach optimizing metabolic status appear to provide the best available alternatives.
#DISCLAIMER
The opinion or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the view of the Department of the Army or the Department of Defense.
#ABBREVIATIONS
-
EC endocannabinoid
-
MS metabolic syndrome
-
NAFLD nonalcoholic fatty liver disease
-
NAS NAFLD activity score
-
NASH nonalcoholic steatohepatitis
-
TZDs thiazolidinediones
-
HFCS high-fructose corn syrup
-
PPAR-γ peroxisomal proliferator activated receptor-gamma
-
SAM S-adenosyl-L-methionine
-
UDCA ursodeoxycholic acid
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- 4 Bugianesi E, Gentilcore E, Manini R et al.. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005; 100 1082-1090
- 5 Singh S P. Non-alcoholic fatty liver disease: the unfolding monster?. J Gastroenterol Hepatol. 2006; 21 199-201
- 6 Marchesini G, Brizi M, Morselli-Labate A M et al.. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med. 1999; 107 450-455
- 7 Falck-Ytter Y, Younossi Z M, Marchesini G, McCullough A J. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis. 2001; 21 17-26
- 8 Day C P, James O F. Steatohepatitis: a tale of two “hits”?. Gastroenterology. 1998; 114 842-845
- 9 Harrison S A, Day C P. Benefits of lifestyle modification in NAFLD. Gut. 2007; 56 1760-1769
- 10 Abdelmalek M F, Diehl A M. Nonalcoholic fatty liver disease as a complication of insulin resistance. Med Clin North Am. 2007; 91 1125-1149
- 11 Bloom S R, Kuhajda F P, Laher I et al.. The obesity epidemic: pharmacological challenges. Mol Interv. 2008; 8 82-98
- 12 Pereira M A, Kartashov A I, Ebbling C B et al.. Fast food habits, weight gain, and insulin resistance (the CARDIA study): 15-year prospective analysis. Lancet. 2005; 365 36-42
- 13 Kechagias S, Ernersson A, Dahlqvist O et al.. Fast-food-based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects. Gut. 2008; 57 649-665
- 14 Bonora E, Kiechl S, Willeit J et al.. Prevalence of insulin resistance in metabolic disorders: the Bruneck study. Diabetes. 1998; 47 1643-1649
- 15 Nielsen S J, Popkin B M. Changes in beverage intake between 1977 and 2001. Am J Prev Med. 2004; 27 205-209
- 16 Elwood P C, Pickering J E, Fehily A M. Milk and dairy consumption, diabetes and the metabolic syndrome: the Caerphilly prospective study. J Epidemiol Community Health. 2007; 61 695-698
- 17 Ouyang X, Cirillo P, Sautin Y et al.. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008; 48 993-999
- 18 Cave M, Deaciuc I, Mendez C et al.. Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutr Biochem. 2007; 18 184-195
- 19 Hickman I J, Jonsson J R, Prins J B et al.. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut. 2004; 53 413-419
- 20 Suzuki A, Lindor K, St Saver J et al.. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J Hepatol. 2005; 43 1060-1066
- 21 Ueno T, Sugawara H, Sujaka K et al.. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol. 1997; 27 103-107
- 22 Tock L, Prado W L, Caranti D A et al.. Nonalcoholic fatty liver disease decrease in obese adolescents after multidisciplinary therapy. Eur J Gastroenterol Hepatol. 2006; 18 1241-1245
- 23 Harrison S A, DiBisceglie A M. Advances in the understanding and treatment of nonalcoholic fatty liver disease. Drugs. 2003; 63 2379-2394
- 24 Lin H Z, Yang S Q, Chuckaree C, Kuhajda F, Ronnet G, Diehl A M. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000; 6 998-1003
- 25 Marchesini G, Brizi M, Bianchi G et al.. Metformin in non-alcoholic steatohepatitis. Lancet. 2001; 358 893-894
- 26 Uygun A, Kadayifci A, Isik A T et al.. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2004; 19 537-544
- 27 Nair S, Diehl A M, Wiseman M, Farr G H, Perrillo R P. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004; 20 23-28
- 28 Caldwell S H, Hespenheide E E, Redick J A et al.. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol. 2001; 96 519-525
- 29 Neuschwander-Tetri B A, Brunt E M, Wehmeier K R, Oliver D, Bacon B R. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003; 38(4) 1008-1017
- 30 Belfort R, Harrison S A, Brown K et al.. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006; 355 2297-2307
- 31 Aithal G P, Aithal G P, Thomas J A et al.. A randomized double blind, placebo controlled trial of one year of pioglitazone in non-diabetic subjects with non-alcoholic steatohepatitis. Hepatology. 2007; 46(suppl 1) 295A
- 32 Thomas J A, Kaye P et al.. A randomized double blind, placebo controlled trial of one year of pioglitazone in non-diabetic subjects with non-alcoholic steatohepatitis. Hepatology. 2007; 46 295A
- 33 Ratziu V, Giral P, Jacqueminet S et al.. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized, placebo-controlled FLIRT trial. Gastroenterology. 2008; 135 100-110
- 34 Nissen S E, Wolski K. The effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular issues. N Engl J Med. 2007; 356 2457-2471
- 35 Murphy C E, Rodgers P T. Effects of thiazolidinediones on bone loss and fracture. Ann Pharmacother. 2007; 41 2014-2018
- 36 Amori R E, Lau J, Pittas A G. Efficacy and safety of incretin therapy in type 2 diabetes mellitus. JAMA. 2007; 298 194-206
- 37 Ding X, Saxena N K, Lin S et al.. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006; 43 173-181
- 38 Tushuizen M E, Brunck M C, Pouwels P J et al.. Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int. 2006; 26 1015-1017
- 39 Baggio L L, Huang Q, Cao X, Drucker D J. An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose homeostasis. Gastroenterology. 2008; 134 1137-1147
- 40 Ekstedt M, Franzen L E, Mathiesen U L et al.. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol. 2007; 47 135-141
- 41 Bhardwaj S S, Chalasani N. Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis. 2007; 11 597-613
- 42 Cohen D E, Anania F A, Chalasani N. National Lipid Association Statin Safety Task Force Liver Expert Panel . An assessment of statin safety by hepatologists. Am J Cardiol. 2006; 97 77C-81C
- 43 Lewis J H, Mortensen M E, Zweig S et al.. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology. 2007; 46 1453-1463
- 44 Vuppalanchi R, Chalasani N. Statins for hyperlipidemia in patients with chronic liver disease: are they safe?. Clin Gastroenterol Hepatol. 2006; 4 838-839
- 45 Chalasani N, Aljadhey H, Kesterson J, Murray M D, Hall S D. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology. 2004; 126 1287-1292
- 46 Rallidis L S, Drakoulis C K, Parasi A S. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis. 2004; 174 193-196
- 47 Lindor K D, Kowdley K V, Heathcote E J et al.. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004; 39 770-778
- 48 Itoh S, Kanazuka A, Akimoto T. Combined treatment with ursodeoxycholic acid and pioglitazone in a patient with NASH associated with type 2 diabetes and psoriasis. Dig Dis Sci. 2003; 48 2182-2186
- 49 Laurin J, Lindor K D, Crippin J S et al.. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology. 1996; 23 1464-1467
- 50 Bauditz J, Schmidt H H, Dippe P, Lochs H, Pirlich M. Non-alcohol induced steatohepatitis in non-obese patients: treatment with ursodeoxycholic acid. Am J Gastroenterol. 2004; 99 959-960
- 51 Vajro P, Mandato C, Franzese A et al.. Vitamin E treatment in pediatric obesity-related liver disease: a randomized study. J Pediatr Gastroenterol Nutr. 2004; 38 48-55
- 52 Lavine J E. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr. 2000; 136 734-738
- 53 Kugelmas M, Hill D B, Vivian B, Marsano L, McClain C J. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology. 2003; 38 413-419
- 54 Harrison S A, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003; 98 2485-2490
- 55 Barak A J, Beckenhauer H C, Junnila M, Tuma D J. Dietary betaine promotes generation of hepatic S-adenosylmethionine and protects the liver from ethanol-induced fatty infiltration. Alcohol Clin Exp Res. 1993; 17 552-555
- 56 Abdelmalek M F, Angulo P, Jorgensen R A, Sylvestre P B, Lindor K D. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol. 2001; 96 2711-2717
- 57 Patrick L. Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment approaches using vitamin E, magnesium, and betaine. Altern Med Rev. 2002; 7 276-291
- 58 Harrison S A, Fincke C, Helinski D, Torgerson S, Hayashi P. A pilot study of orlistat treatment in obese, non-alcoholic steatohepatitis patients. Aliment Pharmacol Ther. 2004; 20 623-628
- 59 Zelber-Sagi S, Kessler A, Brazowsky E et al.. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006; 4 639-644
- 60 Harrison S A, Ramrakhiani S, Brunt E M, Anbari M A, Cortese C, Bacon B R. Orlistat in the treatment of NASH: a case series. Am J Gastroenterol. 2003; 98 926-930
- 61 Banasch M, Goetze O, Schmidt W E, Meier J J. Rimonabant as a novel therapeutic option for nonalcoholic steatohepatitis. Liver Int. 2007; 27 1152-1155
- 62 Woods S C. Role of the endocannabinoid system in regulating cardiovascular and metabolic risk factors. Am J Med. 2007; 120 S19-S25
- 63 Van Gaal L F, Rissanen A M, Scheen A J, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonibant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005; 365 1389-1397
- 64 Pi-Sunyer F X, Aronne L J, Heshmati H M, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiovascular risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006; 295 761-775
- 65 Despres J P, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005; 353 2121-2134
- 66 Scheen A J, Finer N, Hollander P, Jensen M D, Van Gaal L F. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomized controlled study. Lancet. 2006; 368 1660-1672
- 67 Kral J G, Thung S N, Biron S et al.. Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery. 2004; 135 48-58
- 68 Dixon J B, Bhathal P S, Hughes N R, O'Brien P E. Nonalcoholic fatty liver disease: improvement in liver histologic analysis with weight loss. Hepatology. 2004; 39 1647-1654
- 69 Mathurin P, Gonzalez F, Kerdraon O et al.. The evolution of severe steatosis after bariatric surgery is related to insulin resistance. Gastroenterology. 2006; 130 1617-1624
- 70 Furuya C K, de Oliveira C PMS, de Mello E S et al.. Effects of bariatric surgery on nonalcoholic fatty liver disease: preliminary findings after 2 years. J Gastroenterol Hepatol. 2007; 22 510-514
- 71 Mattar S G, Velcu L M, Rabinovitz M et al.. Surgically-induced weight loss significantly improves nonalcoholic fatty liver disease and the metabolic syndrome. Ann Surg. 2005; 242 610-620
- 72 Barker K B, Palekar N A, Bowers S P et al.. Non-alcoholic steatohepatitis: effect of Roux-en-Y gastric bypass surgery. Am J Gastroenterol. 2006; 101 368-373
- 73 de Almeida S R, Rocha P RS, Sanches M D et al.. Roux-en-Y gastric bypass improves the nonalcoholic steatohepatitis (NASH) of morbid obesity. Obes Surg. 2006; 16 270-278
- 74 Clark J M, Alkhuraishi A RA, Solga S et al.. Roux-en-Y gastric bypass improves liver histology in patients with non-alcoholic fatty liver disease. Obes Res. 2005; 13 1180-1186
- 75 Mottin C C, Moretto M, Padoin A V et al.. Histological behavior of hepatic steatosis in morbidly obese patients after weight loss induced by bariatric surgery. Obes Surg. 2005; 15 788-793
- 76 Liu X, Lazenby A J, Clements R H, Jhala N, Abrams G A. Resolution of nonalcoholic steatohepatitis after gastric bypass surgery. Obes Surg. 2007; 17 486-492
- 77 Csendes A, Smok G, Burgos A M. Histologic findings in the liver before and after gastric bypass. Obes Surg. 2006; 16 607-611
- 78 Promrat K, Lutchman G, Uwaifo G I et al.. A pilot study of pioglitazone for the treatment of nonalcoholic steatohepatitis. Hepatology. 2004; 39 188-196
- 79 Sanyal A J, Mofrad P S, Contos M J et al.. A pilot study of vitamin E versus vitamin E and pioglitazaone in the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2004; 2 1107-1115
- 80 Lutchman G, Modi A, Kleiner D E et al.. The effect of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology. 2007; 46 424-429
- 81 Idilman R, Mizrak D, Corapcioglu D et al.. Insulin sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2008; 28 200-208
- 82 Luyckx F H, Desaive C, Thiry A et al.. Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty. Int J Obes Relat Metab Disord. 1998; 22 222-226
- 83 Verna E C, Berk P D. Role of fatty acids in the pathogenesis of obesity and fatty liver: impact of bariatric surgery. Semin Liver Dis. 2008; 28 407-426
Stephen A HarrisonM.D.
Chief of Hepatology, Brooke Army Medical Center
3841 Roger Brooke Drive, Ft. Sam Houston, TX 78234
Email: Stephen.harrison@amedd.army.mil
REFERENCES
- 1 Zelman S. The liver in obesity. AMA Arch Intern Med. 1952; 90 141-156
- 2 Westwater J O, Fainer D. Liver impairment in the obese. Gastroenterology. 1958; 34 686-693
- 3 Ludwig J, Viggiano T R, McGill D B, Oh B J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980; 55 434-438
- 4 Bugianesi E, Gentilcore E, Manini R et al.. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005; 100 1082-1090
- 5 Singh S P. Non-alcoholic fatty liver disease: the unfolding monster?. J Gastroenterol Hepatol. 2006; 21 199-201
- 6 Marchesini G, Brizi M, Morselli-Labate A M et al.. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med. 1999; 107 450-455
- 7 Falck-Ytter Y, Younossi Z M, Marchesini G, McCullough A J. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis. 2001; 21 17-26
- 8 Day C P, James O F. Steatohepatitis: a tale of two “hits”?. Gastroenterology. 1998; 114 842-845
- 9 Harrison S A, Day C P. Benefits of lifestyle modification in NAFLD. Gut. 2007; 56 1760-1769
- 10 Abdelmalek M F, Diehl A M. Nonalcoholic fatty liver disease as a complication of insulin resistance. Med Clin North Am. 2007; 91 1125-1149
- 11 Bloom S R, Kuhajda F P, Laher I et al.. The obesity epidemic: pharmacological challenges. Mol Interv. 2008; 8 82-98
- 12 Pereira M A, Kartashov A I, Ebbling C B et al.. Fast food habits, weight gain, and insulin resistance (the CARDIA study): 15-year prospective analysis. Lancet. 2005; 365 36-42
- 13 Kechagias S, Ernersson A, Dahlqvist O et al.. Fast-food-based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects. Gut. 2008; 57 649-665
- 14 Bonora E, Kiechl S, Willeit J et al.. Prevalence of insulin resistance in metabolic disorders: the Bruneck study. Diabetes. 1998; 47 1643-1649
- 15 Nielsen S J, Popkin B M. Changes in beverage intake between 1977 and 2001. Am J Prev Med. 2004; 27 205-209
- 16 Elwood P C, Pickering J E, Fehily A M. Milk and dairy consumption, diabetes and the metabolic syndrome: the Caerphilly prospective study. J Epidemiol Community Health. 2007; 61 695-698
- 17 Ouyang X, Cirillo P, Sautin Y et al.. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008; 48 993-999
- 18 Cave M, Deaciuc I, Mendez C et al.. Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutr Biochem. 2007; 18 184-195
- 19 Hickman I J, Jonsson J R, Prins J B et al.. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut. 2004; 53 413-419
- 20 Suzuki A, Lindor K, St Saver J et al.. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J Hepatol. 2005; 43 1060-1066
- 21 Ueno T, Sugawara H, Sujaka K et al.. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol. 1997; 27 103-107
- 22 Tock L, Prado W L, Caranti D A et al.. Nonalcoholic fatty liver disease decrease in obese adolescents after multidisciplinary therapy. Eur J Gastroenterol Hepatol. 2006; 18 1241-1245
- 23 Harrison S A, DiBisceglie A M. Advances in the understanding and treatment of nonalcoholic fatty liver disease. Drugs. 2003; 63 2379-2394
- 24 Lin H Z, Yang S Q, Chuckaree C, Kuhajda F, Ronnet G, Diehl A M. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000; 6 998-1003
- 25 Marchesini G, Brizi M, Bianchi G et al.. Metformin in non-alcoholic steatohepatitis. Lancet. 2001; 358 893-894
- 26 Uygun A, Kadayifci A, Isik A T et al.. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2004; 19 537-544
- 27 Nair S, Diehl A M, Wiseman M, Farr G H, Perrillo R P. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004; 20 23-28
- 28 Caldwell S H, Hespenheide E E, Redick J A et al.. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol. 2001; 96 519-525
- 29 Neuschwander-Tetri B A, Brunt E M, Wehmeier K R, Oliver D, Bacon B R. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003; 38(4) 1008-1017
- 30 Belfort R, Harrison S A, Brown K et al.. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006; 355 2297-2307
- 31 Aithal G P, Aithal G P, Thomas J A et al.. A randomized double blind, placebo controlled trial of one year of pioglitazone in non-diabetic subjects with non-alcoholic steatohepatitis. Hepatology. 2007; 46(suppl 1) 295A
- 32 Thomas J A, Kaye P et al.. A randomized double blind, placebo controlled trial of one year of pioglitazone in non-diabetic subjects with non-alcoholic steatohepatitis. Hepatology. 2007; 46 295A
- 33 Ratziu V, Giral P, Jacqueminet S et al.. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized, placebo-controlled FLIRT trial. Gastroenterology. 2008; 135 100-110
- 34 Nissen S E, Wolski K. The effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular issues. N Engl J Med. 2007; 356 2457-2471
- 35 Murphy C E, Rodgers P T. Effects of thiazolidinediones on bone loss and fracture. Ann Pharmacother. 2007; 41 2014-2018
- 36 Amori R E, Lau J, Pittas A G. Efficacy and safety of incretin therapy in type 2 diabetes mellitus. JAMA. 2007; 298 194-206
- 37 Ding X, Saxena N K, Lin S et al.. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006; 43 173-181
- 38 Tushuizen M E, Brunck M C, Pouwels P J et al.. Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int. 2006; 26 1015-1017
- 39 Baggio L L, Huang Q, Cao X, Drucker D J. An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose homeostasis. Gastroenterology. 2008; 134 1137-1147
- 40 Ekstedt M, Franzen L E, Mathiesen U L et al.. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol. 2007; 47 135-141
- 41 Bhardwaj S S, Chalasani N. Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis. 2007; 11 597-613
- 42 Cohen D E, Anania F A, Chalasani N. National Lipid Association Statin Safety Task Force Liver Expert Panel . An assessment of statin safety by hepatologists. Am J Cardiol. 2006; 97 77C-81C
- 43 Lewis J H, Mortensen M E, Zweig S et al.. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology. 2007; 46 1453-1463
- 44 Vuppalanchi R, Chalasani N. Statins for hyperlipidemia in patients with chronic liver disease: are they safe?. Clin Gastroenterol Hepatol. 2006; 4 838-839
- 45 Chalasani N, Aljadhey H, Kesterson J, Murray M D, Hall S D. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology. 2004; 126 1287-1292
- 46 Rallidis L S, Drakoulis C K, Parasi A S. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis. 2004; 174 193-196
- 47 Lindor K D, Kowdley K V, Heathcote E J et al.. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004; 39 770-778
- 48 Itoh S, Kanazuka A, Akimoto T. Combined treatment with ursodeoxycholic acid and pioglitazone in a patient with NASH associated with type 2 diabetes and psoriasis. Dig Dis Sci. 2003; 48 2182-2186
- 49 Laurin J, Lindor K D, Crippin J S et al.. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology. 1996; 23 1464-1467
- 50 Bauditz J, Schmidt H H, Dippe P, Lochs H, Pirlich M. Non-alcohol induced steatohepatitis in non-obese patients: treatment with ursodeoxycholic acid. Am J Gastroenterol. 2004; 99 959-960
- 51 Vajro P, Mandato C, Franzese A et al.. Vitamin E treatment in pediatric obesity-related liver disease: a randomized study. J Pediatr Gastroenterol Nutr. 2004; 38 48-55
- 52 Lavine J E. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr. 2000; 136 734-738
- 53 Kugelmas M, Hill D B, Vivian B, Marsano L, McClain C J. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology. 2003; 38 413-419
- 54 Harrison S A, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003; 98 2485-2490
- 55 Barak A J, Beckenhauer H C, Junnila M, Tuma D J. Dietary betaine promotes generation of hepatic S-adenosylmethionine and protects the liver from ethanol-induced fatty infiltration. Alcohol Clin Exp Res. 1993; 17 552-555
- 56 Abdelmalek M F, Angulo P, Jorgensen R A, Sylvestre P B, Lindor K D. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol. 2001; 96 2711-2717
- 57 Patrick L. Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment approaches using vitamin E, magnesium, and betaine. Altern Med Rev. 2002; 7 276-291
- 58 Harrison S A, Fincke C, Helinski D, Torgerson S, Hayashi P. A pilot study of orlistat treatment in obese, non-alcoholic steatohepatitis patients. Aliment Pharmacol Ther. 2004; 20 623-628
- 59 Zelber-Sagi S, Kessler A, Brazowsky E et al.. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006; 4 639-644
- 60 Harrison S A, Ramrakhiani S, Brunt E M, Anbari M A, Cortese C, Bacon B R. Orlistat in the treatment of NASH: a case series. Am J Gastroenterol. 2003; 98 926-930
- 61 Banasch M, Goetze O, Schmidt W E, Meier J J. Rimonabant as a novel therapeutic option for nonalcoholic steatohepatitis. Liver Int. 2007; 27 1152-1155
- 62 Woods S C. Role of the endocannabinoid system in regulating cardiovascular and metabolic risk factors. Am J Med. 2007; 120 S19-S25
- 63 Van Gaal L F, Rissanen A M, Scheen A J, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonibant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005; 365 1389-1397
- 64 Pi-Sunyer F X, Aronne L J, Heshmati H M, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiovascular risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006; 295 761-775
- 65 Despres J P, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005; 353 2121-2134
- 66 Scheen A J, Finer N, Hollander P, Jensen M D, Van Gaal L F. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomized controlled study. Lancet. 2006; 368 1660-1672
- 67 Kral J G, Thung S N, Biron S et al.. Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery. 2004; 135 48-58
- 68 Dixon J B, Bhathal P S, Hughes N R, O'Brien P E. Nonalcoholic fatty liver disease: improvement in liver histologic analysis with weight loss. Hepatology. 2004; 39 1647-1654
- 69 Mathurin P, Gonzalez F, Kerdraon O et al.. The evolution of severe steatosis after bariatric surgery is related to insulin resistance. Gastroenterology. 2006; 130 1617-1624
- 70 Furuya C K, de Oliveira C PMS, de Mello E S et al.. Effects of bariatric surgery on nonalcoholic fatty liver disease: preliminary findings after 2 years. J Gastroenterol Hepatol. 2007; 22 510-514
- 71 Mattar S G, Velcu L M, Rabinovitz M et al.. Surgically-induced weight loss significantly improves nonalcoholic fatty liver disease and the metabolic syndrome. Ann Surg. 2005; 242 610-620
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Stephen A HarrisonM.D.
Chief of Hepatology, Brooke Army Medical Center
3841 Roger Brooke Drive, Ft. Sam Houston, TX 78234
Email: Stephen.harrison@amedd.army.mil
Figure 1 Insulin resistance and treatment targets in nonalcoholic steatohepatitis.