Fatty Liver and the Metabolic Syndrome

Brent A Neuschwander-Tetri

Curr Opin Gastroenterol. 2007;23(2) 

Abstract and Introduction

Abstract

Purpose of review: Nonalcoholic fatty liver disease and its subset nonalcoholic steatohepatitis represent the liver manifestations of insulin resistance. This review briefly summarizes advances in our understanding of the pathogenesis of nonalcoholic fatty liver disease and its prevalence, natural history and treatment.
Recent findings: The recognition of the role the renin-angiotensin system in promoting insulin resistance is worth noting because of available drugs. Endoplasmic reticulum stress has also become a recent target of investigation because endoplasmic reticulum stress is common in obesity, diabetes and various forms of liver disease including nonalcoholic fatty liver disease. Endoplasmic reticulum stress may be responsible for activation of c-Jun kinase, a process that may cause the hepatocellular injury in nonalcoholic steatohepatitis. Progress has also been made in estimating the prevalence of nonalcoholic fatty liver disease in adults and children. Patients enrolled in the Dallas Heart Study were found to have a 33% prevalence of nonalcoholic fatty liver disease and children dying of accidental deaths in San Diego were found to have a 13% prevalence of nonalcoholic fatty liver disease. Because about 10% of people with nonalcoholic fatty liver disease are at risk for progressive fibrosis, the burden of this disease is now quite substantial.
Summary: Incremental progress in understanding nonalcoholic fatty liver disease and nonalcoholic steatohepatitis promises to lead to new therapeutic options for this common disease.

Introduction

Obesity is now recognized as a major challenge to health, quality of life and longevity in the developed world. The adverse impact of overweight and obesity on the risks for cardiovascular disease, cancer and musculoskeletal disorders is well documented, especially when coupled with components of the metabolic syndrome. More recently recognized is the risk of developing end stage liver disease and hepatocellular cancer as a consequence of nonalcoholic fatty liver disease (NAFLD), the primary hepatic complication of obesity and insulin resistance. Although NAFLD has not been included as a component of the metabolic syndrome as it has been defined, available data indicate that the onset of NAFLD is an early event in the development of insulin resistance and might thus predict the presence or future development of the metabolic syndrome. The purpose of this review is to selectively examine important studies published over the past year that provide new insights into the pathogenesis of NAFLD, its prevalence and its management.

Pathogenesis of Nonalcoholic Fatty Liver Disease

NAFLD is the consequence of excess triglyceride accumulation in hepatocytes in the absence of significant alcohol consumption. How much alcohol constitutes significant consumption will not be discussed here. In some patients with excess fat in the liver, hepatocytes are injured and this sets off a cascade of necroinflammatory changes that include the accumulation of mixed inflammatory cells and hepatocyte ballooning with Mallory body accumulation. A subset of such patients then develops progressive fibrosis that can lead to cirrhosis. Progress in understanding the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) over the past year has primarily been in the area of the mechanisms and treatment of insulin resistance, the underlying abnormality in most patients.

Renin-Angiotensin System

An exciting area of progress is in recognizing that the renin-angiotensin system (RAS) is a major modulator of insulin resistance. Uncontrolled clinical studies have shown that blocking the angiotensin II receptor type 1 (AT1) with losartan improves insulin sensitivity and may be beneficial for NASH. For example, in an uncontrolled study of five patients with impaired glucose tolerance, losartan 100 mg daily for 8 weeks caused the Homeostasis Model Assessment (HOMA) measure of insulin resistance to significantly improve from 5.3 to 3.7.[1*] Seven patients with NASH were similarly treated, but for 48 weeks, and were found to have improved serum aspartate aminotransferase, alanine aminotransferase (ALT), and serum markers of fibrosis.[2] Liver biopsies were also improved[2] and exhibited decreased stellate cell activation.[3*] These provocative early findings now require confirmation in placebo-controlled randomized clinical trials.

Studies in animals have provided some possible mechanistic insights into the role of RAS in insulin resistance, acknowledging the caveat that the RAS in rodents may not fully recapitulate human physiology. Rodents fed a high fructose, high fat diet develop insulin resistance and NAFLD.[4] Recent work by this group showed that rats infused with angiotensin II by osmotic pump or fed a high fructose diet exhibited decreased insulin sensitivity and adiponectin levels.[5] Low levels of adiponectin have been shown in patients with NASH[6] and genetic deletion of adiponectin in mice causes insulin resistance.[7*] In one study of rats, the lower adiponectin levels and impaired insulin sensitivity appeared to be mediated by the receptor AT1 because the AT1-specific angiotensin receptor blocker (ARB) olmesartan improved NAFLD,[4] insulin sensitivity and adiponectin levels.[5]

Specifically examining the role of AT1 is important because the angiotensin II receptor type 2 (identified as AT2, not to be confused with AII which denotes the peptide angiotensin II) mediates important effects of angiotensin, often in ways that oppose AT1 signaling.[8] The studies in angiotensin treated or fructose fed rats described above specifically demonstrated that AT2 was not responsible for the insulin resistance and decreased adiponectin levels by the use of AT2 agonists and receptor blockers.[5] On the other hand, seminal work by Hsieh has shown that while AT1 mediates hepatic insulin resistance in fructose fed rats, this effect of AT1 requires coactivation of AT2.[9,10]

A provocative study of the ARB telmisartan in fructose fed rats demonstrated that treated rats not only accumulated less fat in the liver, but that this particular ARB also increased energy expenditure and prevented weight gain.[11**] Some have argued that many of the beneficial effects of telmisartan are due to its unique (among ARBs) PPARγ ligand effects,[12*] while others believe that its effects are mediated primarily via its ARB properties.[13*] Either way, telmisartan appears to be an agent particularly worthy of study in patients with NASH to determine if these benefits in rodents translate into similar benefits in humans.

Adipokines and Cytokines

Other studies have provided new insights into mechanisms of fat accumulation in NAFLD. Abnormalities in cytokine and adipokine signaling have been found and incremental advances have been made over the past year. Resistin, an adipokine identified in mice, continues to be studied and a new marker of insulin resistance, retinol binding protein (RBP)-1, has been described.

Resistin is an adipocyte derived peptide, or adipokine, that induces insulin resistance in all of the major targets of insulin: liver, muscle and adipose tissue. First identified and further characterized in mice,[14] its role in human metabolism has been uncertain.[15] A small study of NAFLD patients treated with pioglitazone demonstrated improved insulin sensitivity and reduced resistin levels,[16] but a more recent study[17*] showed that resistin levels in humans correlate with necroinflammatory changes of NASH rather than insulin sensitivity. Another study[18*] demonstrated that circulating resistin levels in humans were elevated in patients with cirrhosis and may be a major mediator of the insulin resistance known to occur in cirrhosis. Thus, the role of resistin as a mediator of insulin resistance in NAFLD patients remains uncertain.

RBP4 is a newly recognized adipocyte-derived mediator of insulin resistance in muscle and liver.[19**] To expand on studies that characterized this adipokine in mice, Graham et al. [20**] measured serum RPB4 levels in groups of patients and found that increased RBP levels strongly correlated with the degree of insulin resistance, concluding that levels of this adipokine could be used as a good surrogate marker of insulin resistance. Ongoing studies are examining the levels of RBP4 in patients with NAFLD.

Gut Flora and Insulin Resistance

A number of studies have suggested that gut-derived endotoxin could play a role in the pathogenesis of insulin resistance and NAFLD,[21] although altering bowel flora is not generally embraced as a treatment option for NASH. An alternative hypothesis is suggested by a new study of two strains of mice that differ in their development of insulin resistance and NAFLD on a high fat diet. Mice that develop NAFLD were found to have choline deficiency caused by strain-specific breakdown of choline by gut flora leading to a deficiency that could predispose to insulin resistance and NAFLD.[22*] Choline deficiency has been proposed to be a cause of NAFLD in patients receiving total parenteral nutrition without adequate choline supplementation,[23] but whether choline supplementation could be helpful in NAFLD needs further evaluation.

Hepatocellular Injury in Nonalcoholic Steatohepatitis

Only a fraction, possibly about a third, of patients with NAFLD also develops substantial necroinflammatory changes that meet current criteria for NASH. These criteria have been laid out for the purposes of clinical studies in the description of a validated scoring system for NAFLD.[24*] The role of inflammation in NAFLD and NASH has been reviewed recently in this journal[25] and will not be further discussed here.

Mitochondrial Abnormalities

Mitochondrial dysfunction has been proposed to be one of the primary defects in NASH.[26*] Seminal work by Shulman has identified muscle mitochondrial dysfunction among young lean children of diabetic patients long before the onset of diabetes.[27,28**] Interestingly, defects in insulin-stimulated muscle phosphate uptake have also been identified by this group, raising the question of whether impaired mitochondrial ATP synthesis could be caused by insufficient intracellular phosphate.[29**] These studies raise a provocative possibility that genetic defects of muscle energy metabolism might not only predispose to insulin resistance and its sequelae, but they could also cause exercise intolerance beginning early in life that would predispose to a sedentary lifestyle. Evidence of muscle dysfunction and injury in NASH patients has been slowly emerging with the finding of extraocular muscle dysfunction[30] and unexplained serum creatine kinase elevations in small series of NASH patients.[31]

Endoplasmic Reticulum Stress

Another area of rapidly expanding knowledge is in the role of endoplasmic reticulum stress as a cause of insulin resistance and NAFLD. The smooth endoplasmic reticulum is where proteins are processed into their final form and if the flux of proteins through the endoplasmic reticulum overwhelms its processing capacity or if defective proteins impair endoplasmic reticulum processing (as can be the case with abnormal a-1 antitrypsin variants), a stress response can initiate the process of cellular death through apoptosis. Endoplasmic reticulum stress has now been implicated not only in the development of insulin resistance and diabetes,[32] but also of various forms of liver disease including NASH.[33*] This opens up a new arena of therapeutic options. Small molecule endoplasmic reticulum chaperones that help reduce endoplasmic reticulum stress have been shown to improve insulin resistance and NAFLD in genetically obese and high fat diet-fed mice,[34**] although the doses used were quite large and may not translate into viable alternatives for human use.

Prevalence

If fatty liver disease were not so common and if it did not progress to cirrhosis, death, transplantion and hepatocellular carcinoma, it would be a benign condition of little consequence other than occasional right upper quadrant abdominal pain. But it is not rare and it is not benign. Previous epidemiologic evidence has suggested that about 20% of adults have NAFLD and 3-4% of adults have NASH, with a third of those or 1% of adults having fibrosis and thus being at risk for progressing to cirrhosis.[35] The most recent data are provided by the Dallas Heart Study which measured liver fat content by magnetic resonance spectroscopy in 2349 adults and found excess liver fat in 33.6%.[36**] Whether this higher prevalence figure for NAFLD in adults reflects more stringent criteria or increasing prevalence with time is uncertain. Either way, the prevalence of NAFLD in adults is alarmingly large. Similar epidemiological data have been difficult to acquire in children. One approach by Schwimmer et al. [37**] was to determine the prevalence of NAFLD in children dying accidental deaths. In this study of 742 children aged 2-19 years, NAFLD was found in 13% of subjects with the prevalence increasing with age and obesity.

Emerging data indicate that there are significant racial and ethnic differences in the risks for NAFLD and cryptogenic cirrhosis. Both appear to be overrepresented in North American Hispanics and underrepresented in African Americans compared to the population as a whole,[38,39*] although the basis for these striking differences remains enigmatic.

Natural History and Risk Factors for Progressive Liver Disease

The natural history of NASH has been impossible to establish for two reasons. First, once the diagnosis is established, the natural history of this disease can be dramatically altered because of increased medical attention and lifestyle modifications among patients concerned enough to undergo liver biopsy. Second, the diagnosis may be missed or classified as cryptogenic cirrhosis in patients dying from other complications of the metabolic syndrome such as coronary heart disease.

Recent data confirm an increased risk of death from vascular disease in patients with NAFLD and NASH.[40] An epidemiologic study conducted at Mayo found that the risk of death from liver disease was increased in NASH patients, but also a quarter of NASH patients died from ischemic heart disease.[41] Moreover, analysis of the NHANES III data set identified unexplained elevations of serum ALT as a risk for heart disease, especially among women.[42]

Management

The treatment options for the metabolic syndrome and their impact on NAFLD have been reviewed extensively elsewhere[43**] and only a few points regarding weight loss will be made here.

Weight Loss: Drugs

Lifestyle modifications comprising healthy eating habits and regular exercise are the primary interventions recommended to patients with NAFLD. Weight loss can be facilitated by the enteric lipase inhibitor orlistat, and a randomized clinical trial of 52 NASH patients treated for 6 months found that orlistat improved serum ALT levels and steatosis more than lifestyle modification alone.[44] The endocannabinoid receptor antagonist rimonabant is also now being evaluated as a possible treatment for NASH based on its ability to induce weight loss,[45,46] although side effects remain a concern.[47]

Weight Loss: Bariatric Surgery

When all else fails, as it too often does, dietary portion control can be enforced by surgical alteration of the stomach. Bariatric surgery was recently reviewed in this journal.[48] The impact of bariatric surgery on liver disease has been a focus of multiple studies because of the liver disease induced by the jejunoileal bypass technique used three decades ago. The current techniques of gastric banding and Roux-en-Y gastric bypass surgery have not been associated with progressive liver disease. In fact a number of studies published just in the past year suggest that NASH improves with weight loss and improved insulin sensitivity following bariatric surgery.[49-53]

Special Issues

Because of the increasing prevalence of components of the metabolic syndrome, clinicians must often wrestle with issues of drug toxicity and surgical risks in patients with NAFLD. Fortunately, newer data provide some guidelines that can help inform the management of such patients.

Use of Statins

The statin class of drugs used to treat hypercholesterolemia is associated with relatively common but mild elevations of aminotransferases, rare idiosyncratic severe hepatotoxicity and rhabdomyolysis. The presumption that the aminotransferase elevations could be harbingers of subsequent severe hepatotoxicity led to cautions by the drug manufacturers to avoid the use of these drugs in patients with preexisting liver enzyme elevations, warnings that in retrospect were unfounded.[54**] A review of a national insurance claims database found no evidence that such warnings had any scientific basis, although the use of CYP3A4 inhibitors appeared to increase the risk of rhabdomyolysis.[55] A careful review of all of the data by an expert panel concluded that statins are safe in patients with preexisting liver disease except for those with decompensated cirrhosis or acute liver failure, patients in whom there are no data but extra caution is warranted.[56**] Emerging data suggest that there might even be a role of statins in the treatment of NASH.[57]

Use of Tamoxifen

Earlier studies clearly documented that NASH is overrepresented in women taking tamoxifen following resection of breast cancer and that imaging evidence of NAFLD can develop during treatment with tamoxifen. To help focus surveillance for unsuspected liver disease within this large cohort of women, a recent study[58*] found that NAFLD appears to be limited to those with obesity and components of the metabolic syndrome. Although this study did not identify progressive disease over a relatively short period, continued monitoring of patients at risk would be prudent.

Surgical Risk

Establishing surgical risk in patients with liver disease is challenging because of the heterogeneity of abnormalities associated with liver disease such as shunting, diminished synthetic function, sensitivity to hypoxia, and portal hypertension, each having its own consequences in terms of surgical risk. Cho et al.[59] examined the impact of NAFLD (5-30% fat compared to under 5% fat) on the outcomes after donor partial hepatectomy surgery. The presence of such mild steatosis did not have an adverse impact on donor survival or adverse outcomes. Interestingly, imaging evidence of NAFLD rapidly diminished in the postoperative regenerative period. Another study did observe increased 90-day mortality associated with the presence of NASH in patients undergoing resection of colorectal metastatic lesions in the liver.[60] The presence of NASH at the time of surgery was also associated with the use of the chemotherapeutic agent irinotecan in the preoperative period, raising the possibilities that these patients were selected for more advanced disease or that the drug itself was responsible for the poorer outcome.

Conclusion

Advances in our understanding of the pathogenesis of NAFLD and NASH continue to be made and give us hope that new therapeutic options will soon be available. Such options are certainly needed because of the failure or inability of many to sustain lifestyle modifications and the enormous burden of this disease in our society.

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