From Southern Medical Journal
Lakshmi Pasumarthy, MD, FACP; James Srour, MD
Posted: 08/05/2010; South Med J. 2010;103(6):547-550. © 2010 Lippincott Williams & Wilkins
Abstract and Introduction
Abstract
Nonalcoholic steatohepatitis is a common cause of liver inflammation and is associated with obesity, insulin resistance, and hyperlipidemia. There are concerns that it may turn out to be the most common cause of liver failure as prevalence of obesity increases. It leads to increased morbidity and mortality. Other causes of liver inflammation, especially alcoholic liver disease, must be ruled out. The diagnosis is suggested by abnormalities in the blood work and metabolic panel in an obese patient. Despite advances made in our understanding regarding the pathogenesis and trials with multiple drugs targeting mechanisms in pathogenesis, there are no consistent guidelines regarding treatment. However, multiple sources advocate weight reduction, optimum blood glucose control, and elimination of medications that cause fatty infiltration. The purpose of our article is to detail advances made in identifying disease mechanisms and treatment modalities, including surgery to promote weight loss.
Introduction
Fatty infiltration of the liver was described a long time ago and was initially felt to be linked with alcohol-related liver damage. The term nonalcoholic steatohepatitis (NASH) was introduced by Ludwig in 1980 and recognized in the absence of alcohol intake.[1] In the 1990s the incidence of nonalcoholic fatty liver disease (NAFLD) began to increase, paralleling the increase in obesity rates, and it is now recognized widely. The entity includes NAFLD which presents with simple steatosis, NASH, and cirrhosis. It is the most common cause of chronic liver disease. The estimated prevalence of NAFLD and NASH is 20–30% and 3.5–5%, respectively.[2] There is a higher prevalence of NASH in Mexican-Americans compared with non-Hispanic whites, even after controlling for obesity and body fat distribution.[3] The importance of NASH becomes more apparent when reviewing available data, which shows that 10–15% of patients with histologically proven NASH progress to cirrhosis and its complications such as liver failure and hepatocellular carcinoma. Furthermore, patients with NASH have lower survival rates.[4] Unfortunately, even though the prevalence of NASH threatens to increase, there are no approved medications for its treatment. There are many medications being evaluated currently, many targeting different steps in the development of hepatic steatosis or its progression to steatohepatitis. The laboratory and histologic profile of NASH and alcoholic liver disease are very similar. Distinction should be made carefully, since the treatment and prognosis are quite different.
Pathogenesis
The "two hit" hypothesis is a commonly described pathway by which fatty liver progresses to nonalcoholic steatohepatitis (NASH). The first hit involves macrovesiclular steatosis due to increased hepatic lipid synthesis and reduced transfer of lipids from the liver. Though insulin resistance plays an important role in this process, once the steatosis develops, it frequently worsens the insulin resistance and triggers a vicious cycle.[5] The role of insulin resistance in the pathogenesis of this disease is supported by pilot studies demonstrating beneficial effects of glucose-sensitizing medications in patients with NASH. Receptors in the cell nucleus that are involved in triggering the effects of insulin may fail, thus leading to insulin resistance, hepatic inflammation, and, ultimately, hepatic scarring. Treatment with rosiglitazone reduces the expression of hepatic acute phase reactants (C-reactive protein and serum amyloid A), suggesting that improvements in insulin sensitivity correspond with a reduction in inflammation.[6]
The second hit occurs due to increased hepatic oxidative stress, perhaps arising from increased free fatty acid metabolism, decreased antioxidant activity, increased activity of mitochondrial uncoupling proteins, and/or increased endotoxin levels in the liver. Oxidative stresses—mainly as a consequence of mitochondrial dysfunction—and proinflammatory cytokines are thought to play a central role in the progression from simple steatosis to steatohepatitis and cirrhosis.[7]
Accumulating evidence supports the role of antioxidants in preventing oxidative liver injury. In a study by Harrison et al,[8] a 6-month course of combination therapy with vitamin E and vitamin C resulted in significant histologic improvement. In another study, dietary intake of antioxidant vitamins was significantly lower in patients with NASH compared with controls matched for age and body mass index.[9] Genetic causes of increased fatty acid input promote excessive hepatic lipogenesis. These include mutations that cause leptin deficiency or leptin receptor inhibition and mutations that induce insulin, insulin-like growth factors, or insulin-responsive transcription factors.[10] Leptin signals "fullness" postprandially and also promotes insulin sensitivity. Despite elevated plasma levels of leptin, patients with NASH often do not experience normal satiety, and they also have insulin resistance. Thus, hyperinsulinemia and defective leptin signaling are conspicuous at early stages of NASH. It has also been shown that leptin is clearly related to stellate cell activation.[11] Inflammation of hepatocytes causes activation of hepatic stellate cells which are important in the pathogenesis of fibrosis. Increased levels of insulin cause upregulation of fibrogenic growth factor secreted by the hepatic stellate cells.
There is evidence to support the hypothesis that angiotensin II promotes activation, and dedifferentiation of the stellate cells into myofibroblasts. Furthermore, angiotensin II encourages myofibroblast contraction and proliferation and promotes release of inflammatory cytokines as well as the deposition of extracellular matrix.[12]
Presentation
Type 2 diabetes, insulin resistance, central obesity, and dyslipidemia are risk factors associated with development of NASH.[13] Initially, most patients with NASH are asymptomatic and present with abnormal liver tests obtained after routine screening. Rarely patients present with symptoms such as fatigue and nonspecific right upper quadrant pain. A careful history to exclude significant alcohol intake is extremely important.[14] This is defined as more than two alcoholic drinks a day for a male (20 gm/day) and more than one alcoholic drink a day for a female (10 gm/day). Fatty infiltration is also found in the context of other liver disorders, therefore it is important to go through the differential diagnoses. Finally, it is important to review the patient's medication list including over the counter medications, herbal remedies, and vitamin supplements. Many drugs can precipitate or exacerbate steatohepatitis in the presence of other risk factors.
As the fibrosis advances, the patients present with the typical manifestations of cirrhosis such as spider telangiectasiae, ascites, ankle edema, and easy bruising. It has been proposed that what was once classified as cryptogenic cirrhosis was probably underrecognized "burned out" NASH.
Diagnosis
The diagnosis of NAFLD is suspected in patients with elevated aminotransferases and evidence of the metabolic syndrome, although the levels fluctuate and patients may have normal enzyme levels on several occasions. The distinction between NASH and simple steatosis cannot reliably be made without liver biopsy, but this is not practical as a population-based approach.[15]
A multivariable model that included age, body mass index, platelet count, albumin, and aspartate aminotransferase/alanine transaminase (AST/ALT) ratio had good discriminant ability to identify individuals with advanced fibrosis in a study of 733 patients.[16] In addition, the diagnosis is suggested by ruling out other causes of elevated liver enzymes coupled with the patient's metabolic profile.
In NAFLD, the alanine aminotransferase (ALT) is initially greater than the aspartate aminotransferase (AST), and the trend is found reversing with onset of cirrhosis.[17] Transaminase values are usually increased less than fourfold, though normal values do not exclude the diagnosis. These values correlate poorly with the severity of underlying liver disease. Interest has been generated by SteatoTest for the diagnosis of hepatic steatosis and by NashTest for the diagnosis of NASH. These tests utilize noninvasive biomarkers such as gamma glutamyl-transferase (GGTP), total bilirubin, haptoglobin, α2-macroglobulin, and apolipoprotein A1. However, these are still not recommended in routine clinical practice.[18]
There is no single pathognomonic histological lesion in NASH and, instead, the disease presents with a constellation of findings. Three histological lesions are necessary for the diagnosis of NASH: zone 3 macrosteatosis, hepatocyte ballooning, and mixed lobular inflammation. Other findings that are common, but not necessary, include mild-moderate portal inflammation, acidophil bodies, glycogenated nuclei, periodic acid stain after diastase Kupffer cells, lipogranulomas and perisinusoidal zone 3 fibrosis, and Mallory hyaline in hepatocytes and megamitochondria.[19] A liver biopsy yields a very small sample of the liver and may not accurately reflect the extent or diagnosis because the histological lesions of NASH are unevenly distributed throughout the liver parenchyma.[20]
Noninvasive radiologic modalities like ultrasound (US), computerized tomography (CT) and magnetic resonance imaging (MRI) are sensitive in diagnosing steatosis but they are not able to differentiate the nonprogressive form of NAFLD from fibrosis.[21] CT and US are very sensitive only when there is more than 33% fat in the hepatic parenchyma.
Treatment
Nonpharmacologic
Factors that increase hepatic oxidative stress promote progression from hepatic steatosis to steatohepatitis. Avoidance of alcohol, weight loss, a low-fat diet, exercise, and tight glycemic control of diabetes help inhibit disease progression.
Weight loss as achieved through diet and exercise should be gradual, aiming for no more than 2 lbs of weight loss per week. Weight loss and exercise help improve insulin resistance. Exercise can also improve muscular insulin sensitivity, which may improve the impact of insulin resistance on NASH.
Though weight loss is rapid, bariatric surgery for morbid obesity does help NASH significantly. For example, Dixon et al showed that NASH resolved in 82% of patients undergoing laparoscopic adjustable gastric banding after losing approximately 40 kg. Patients who had metabolic syndrome showed a greater improvement in steatosis, necroinflammation, and fibrosis with weight loss showcasing the fact that improvements in several components of metabolic syndrome are expected to have a beneficial impact on the liver disease. This is probably because of the decrease in cytokines and chronic inflammation associated with obesity.[22]
Pharmacologic
Orlistat/Sibutramine. A clinical trial using orlistat showed a mean decrease in body weight of 10.3 kg and significant reductions in serum transaminase levels in obese patients with NASH. A 6-month pilot study of sibutramine reported weight loss, improved insulin resistance, and biochemical profiles.[23]
Vitamins. Some hepatologists utilize vitamin E based on trials in which decrements in ALT were demonstrated either with vitamin E alone or in combination with pioglitazone or with vitamin C.[8,24,25] However, given more recent concerns related to an increase in mortality with vitamin E supplementation and the weak evidence supporting its benefit in NASH, vitamin E is not advocated strongly.
Medications Addressing Insulin Resistance. Metformin and thiazolidinediones are insulin sensitizing and work by decreasing insulin resistance. Since this issue is closely associated with the pathogenesis of NASH, much interest and work has been devoted to these medications.
Metformin acts by decreasing hepatic glucose production and increasing peripheral glucose uptake by muscles. Metformin can also increase fatty acid oxidation and suppress lipogenesis. Trials involving lipid and calorie-restricted diet with or without metformin for six months[26] showed decreased aminotransferase levels, insulin, and C-peptide levels to a significantly greater extent in the metformin group. In another randomized trial, metformin alone resulted in normalization of aminotransferases as compared with vitamin E and weight loss. Despite some gastrointestinal intolerance, metformin was well tolerated. On the other hand, though biochemical improvement was shown, histological data remain very limited. It must be avoided in patients with congestive heart failure and renal insufficiency.[27]
Thiazolidinediones reduce insulin resistance by acting on peroxisome proliferator-activated receptors (PPAR)—gamma in adipose tissue. Both pioglitazone and rosiglitazone have been studied and demonsrated improvements in transaminases and liver histology in multiple studies[28,29] Concerns for cardiovascular effects, congestive heart failure and weight gain have limited their long term use. Nateglinide, muraglitazar, and rimonabant have helped with weight loss in the obese but data to support their use for NASH are limited.
Lipid Lowering Medications. Both fibrates and statins have been studied for treatment of NASH since hyperlipidemia is one of the components of metabolic syndrome. Gemfibrozil has shown an improvement in aminotransferases in a trial, though no other fibrate has replicated this result. Fibrates have a complex mechanism of action affecting several pathways resulting in lowering triglycerides and increasing high-density lipoprotein (HDL).[30]
Both pravastatin and atorvastatin act by inhibiting hydroxymethylglutaryl-CoA reductase, a key step in cholesterol metabolism, and showed an improvement in aminotransferases and, as expected, in the lipid panels.[31,32] The use of statins raises concerns for hepatotoxicity, but this was not seen with standard doses used in the study.[33]
Antioxidants. Vitamins E and C are mentioned above.
Betaine is a metabolite of choline that assists with the synthesis of S-adenosylmethionine, which is a powerful antioxidant. It has been studied in a small trial and showed improvements in liver biochemistries and histology.[34]
Tumor necrosis factor (TNF)-α is a pro-inflammatory mediator and plays a distinct role in hepatocyte inflammation and cell death. Pentoxifylline is a TNF-α inhibitor and has shown improvement in transaminases and insulin resistance; nausea was also a significant concern.[35]
Ursodeoxycholic acid (UDCA) is a cytoprotective medication tried by Lindor and coworkers[36] and did not reveal any significant benefits in a double-blind, placebo-controlled trial.
Others. Animal studies have demonstrated a marked decrease in hepatic fibrosis and stellate cell activation with inhibition of renin-angiotensin system. Stellate cells are important in the pathogenesis of liver fibrosis. Losartan has been studied in patients with NASH and hypertension and has shown improvements in markers of fibrosis.[37]
Conclusion
In summary, NASH is poised to become the leading cause of liver failure and continues to be the source of much discussion regarding the etiopathogenesis. Though many medicines have been evaluated closely and more are being researched, there are no uniform guidelines for treatment. The main focus of treatment still involves weight loss, and modifying risks such as insulin resistance.
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