Author:
Heiner Wedemeyer, MD, Michael P. Manns, MD; Medscape Gastroenterology 5(2), 2003
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Date Posted: Wed, October 08 2003, 8:33:22 PDT
Introduction
Fatty liver disease has received markedly increasing attention in recent years.[1] This may be explained by the fact that nonalcoholic steatohepatitis (NASH) is more and more frequently recognized as being a condition that potentially could lead to advanced liver fibrosis in a substantial proportion of cases. Recently it has been estimated that up to 9 million individuals in the United States suffer from nonalcoholic fatty liver disease (NAFLD). However, in only a minority of patients can steatosis be explained by alcohol consumption or viral infections. Our knowledge of disease pathogenesis has increased significantly in the last decade, potentially leading to new therapeutic options that are currently being explored in clinical trials.
At this year's meeting of the European Association for the Study of the Liver (EASL), which initially was to have been held in Istanbul, Turkey, in March but was postponed and reconvened in Geneva from July 3-6 because of world circumstances, NAFLD was one of the major topics of focus besides viral hepatitis. The EASL President's premeeting, entitled "Nonalcoholic Fatty Liver Disease: From Innocent Bystander to Progressive Fibrosis and Cirrhosis," was reflective of the latter. In addition, several interesting new studies were presented during the core meeting proceedings that investigated both basic and clinical aspects of steatosis and steatohepatitis.
This report discusses a select subset of these presentations that we believe contribute significantly to our understanding, diagnosis, and therapy of alcoholic and nonalcoholic fatty liver disease.
Definition of NAFLD, NASH, and ASH
NAFLD includes a spectrum of disorders characterized mainly by macrovesicular hepatic steatosis.[2] NAFLD can represent a broad spectrum of hepatic pathology, ranging from simple steatosis without any evidence of inflammation, to severe inflammatory activity with significant fibrosis or even cirrhosis.[3] The combination of steatosis and inflammation are the hallmarks of nonalcoholic steatohepatitis (NASH). Thus, to establish the diagnosis of NASH, a liver biopsy is, by definition, required.
NASH was first characterized by Ludwig and coworkers[4] at the Mayo Clinic in 1980. The differentiation of NASH from alcoholic steatohepatitis (ASH) may be difficult, because it is not known how much alcohol consumption is required to induce steatosis with inflammation. The amount of alcohol may vary with sex and genetic factors as well as with the capacity of antioxidative defense mechanisms. However, if ongoing alcohol consumption (of less than 20-30g per day) can be excluded, the diagnosis of NASH becomes likely.
Diagnosis of NAFLD and NASH
An overview on the current state of the art of diagnosis of NAFLD was presented during the President's premeeting by Peter Ferenci[5] of Vienna, Austria. Hepatic fat accumulation can be demonstrated by ultrasonography, computerized tomography (CT), or magnetic resonance imaging; however, none of these methods provides information on the fine architecture of liver tissue or on the etiology of steatosis. Even hepatic fat accumulation, as diagnosed by an imaging technique, along with the finding of elevated aminotransferase levels are not sufficient to distinguish between fatty liver alone and NASH.[4] Thus, for the diagnosis of NASH to be established, a liver biopsy is still required and therefore remains the gold standard. Only information from biopsy allows grading and staging of the disease, as emphasized by pathologist Elizabeth Brunt[6] of the United States. This latter information is crucial for patient management because simple nonalcoholic fatty livers have a benign prognosis, whereas NASH can be progressive and lead to end-stage liver disease.
Typical histologic features of NASH primarily include macrovesicular steatosis, a mixed lobular inflammation, and hepatocellular ballooning. Frequent findings also include lipogranulomas in the lobules and acidophil bodies, as well as perisinusoidal fibrosis. Mallory bodies can be found in NASH in zone 3, whereas Mallory's hyaline in ballooned hepatocytes in zone 1 is more typical for diabetes- or amiodarone-induced steatohepatitis.[3] A scoring system to grade and stage NASH was proposed by Dr. Brunt[7] in 1999. Whereas grading not only takes the amount of fat accumulation into account but also considers ballooning and inflammation, staging from 1 to 4 is similar to scoring systems used for viral hepatitis[8,9] and distinguishes between perisinusoidal fibrosis, portal-based fibrosis, bridging fibrosis, and cirrhosis (Table 1).
In the search for noninvasive methods of grading NASH, a Turkish group from Elazig explored whether calibrated CT might substitute for liver biopsies.[10] Data from 19 patients with histologically proven NASH who underwent CT were presented, and, interestingly, a linear correlation between CT scan density and histopathologic grade (r:-0.70) and stage (r:-0.51) was noted. Although these data must be confirmed in larger series, noninvasive grading and staging of NASH may be possible in the near future.
Currently, a liver biopsy is still required to confirm the diagnosis of NASH, as was demonstrated in a study from England presented during these meeting proceedings, in which 41 of 82 patients with NAFLD showed significant fibrosis on biopsy.[11] However, in contrast to the requirement of biopsies for primary diagnosis, for the majority of patients with NAFLD, there is now need for repeated liver biopsies after diagnosis has been confirmed, as highlighted by Dr. Ferenci.[5] Patient management and control of treatment success can be monitored with biochemical liver function tests. If the cause of the steatosis is abolished, results of imaging studies should show normal hepatic architecture over time.
Pathogenesis and Natural History of NAFLD and NASH
Christopher Day[12] of Newcastle upon Tyne, United Kingdom, reviewed the pathogenesis of steatohepatitis during the President's premeeting program. He proposed a modification of the classical "2-hit model" of NASH pathogenesis. This model considered steatosis as the "first hit," followed by a "second hit" leading to hepatocyte injury and inflammation. It has been shown that the severity of fat accumulation correlates with activation of hepatic stellate cells, thus, steatosis per se may activate fibrogenesis. Steatosis then "sensitizes" the liver to the second hit. Candidates for the "second hit" include oxidative stress (eg, reactive oxygen species induce the expression of proinflammatory molecules and proapoptotic molecules such as Fas ligand), several different cytokines, or endotoxins. Dr. Day summarized data suggesting that the link between obesity, insulin resistance, and the risk of NASH might be explained by increased release of free fatty acids from adipose tissue.
A number of studies have shown that the majority of NASH patients are obese and that one fourth to one half of these patients suffer from type 2 diabetes.[13-15] It is also widely accepted that insulin resistance is a universal finding in patients with NAFLD. During this year's EASL meeting, several studies were presented that analyzed large cohorts (involving from 270 to more than 400 patients with NASH) for characteristics and possible links to the metabolic syndrome and insulin resistance. One group from Italy confirmed that insulin resistance -- but not insulin secretion -- is associated with NAFLD.[16] In another Italian cohort from Turin and Bologna, metabolic syndrome was found to be present in a large proportion of patients with NAFLD, including nonobese, nondiabetic individuals. In turn, the presence of NASH was found to be associated with metabolic syndrome.[17] However, few patients with NASH did not show any of the characteristics of the metabolic syndrome, and only 25% of patients with metabolic syndrome have NASH; only a minority of obese patients progress to NASH. Thus, individual environmental and genetic factors are clearly important for progression to NASH. Candidate genes include genes determining the magnitude and pattern of obesity (11-beta hydroxysteroid dehydrogenase type I), genes determining insulin sensitivity (PPAR [peroxisome proliferator-activated receptor]-gamma), genes involved in hepatic lipid storage (apolipoprotein E, microsomal triglyceride transfer protein), genes involved in fatty acid oxidation (CYPs [cytochrome P450s], PPAR-alfa, acyl-CoA oxidase), cytokine genes (IL [interleukin]-4, TGF [transforming growth factor]-beta, IL-10, IFN [interferon]-gamma, TNF [tumor necrosis factor]-alpha), genes influencing oxidative stress (HFE, TNF-alpha), and genes encoding proteins involved in response to oxidative stress (MnSOD [manganese superoxide dismutase], UCP [uncoupling protein]-2).
Ghrelin is a hormone that induces release of growth hormone, adrenocorticotropic hormone, and cortisol, and thereby increases food intake and body weight. The role of ghrelin in NASH was investigated by Elisabetta Bugianesi and colleagues.[18] They found that ghrelin is elevated in patients with NAFLD -- and, interestingly, primarily in those patients with normal body weight -- but that it is not associated with insulin resistance and/or disease activity. Thus, ghrelin is not likely to be a key mediator in the pathogenesis of fatty liver disease.
Our knowledge regarding progression rates from steatosis to NASH and from NASH to cirrhosis has significantly improved.[19] It has become clear that "simple" steatosis rarely progresses to NASH unless a "second hit" occurs. However, once NASH has been established, a significant proportion of patients may develop significant fibrosis and cirrhosis (up to 25% in follow-up studies). Moreover, many cases of previously termed "cryptogenic" cirrhosis may be explained by steatohepatitis.[20] Recently published studies[21] as well as reports presented during this year's EASL meeting[22] suggest that even patients with normal aminotransferase levels and steatosis may have inflammatory activity and signs of fibrosis. This leads to the dilemma of how to proceed with patients who have signs of steatosis on ultrasound examination but normal alanine aminotransferase (ALT) values. Should we biopsy all of these patients? Of course we first have to ask whether the biopsy will have any therapeutic consequence. Asking patients to lose some weight and increase their exercise would be good advice regardless. It may then be wise to screen these individuals for insulin resistance before treatment with insulin-sensitizing agents is started
Treatment
Restricted Diet and Exercise
The primary treatment strategies for NASH are weight loss and physical activity.[23,24] In 1997, the results of one study demonstrated the beneficial effect of restricted diet and exercise in obese patients with fatty liver.[25] These data were confirmed by results of a study presented during this year's meeting proceedings by a group from Japan.[26] Seventeen patients with NASH followed a program of restricted diet and exercise (walking or jogging for 40 minutes per day) for 3-6 months. Liver biopsies taken after treatment showed that body mass index, aspartate aminotransferase (AST) and ALT levels, and histologic findings such as steatosis, lobular inflammation, and lipogranuloma, improved significantly. However, there was no significant difference in the degree of fibrosis -- thus this conservative approach seems to require more time to induce regression of liver fibrosis in patients with NASH. These small trials and others summarized by Dr. Bugianesi[23] suggest that even in the absence of randomized controlled trials, obese patients with NASH should be advised to lose weight by calorie restriction and with increased exercise. However, weight loss should not exceed 1 kg per week because more rapid weight loss may cause exacerbation of liver disease. In some cases, pharmacologic regimens may be considered for markedly obese patients, as was recently reported.[27]
Insulin-Sensitizing Agents
As mentioned above, insulin resistance is thought to play a key role in the pathogenesis of steatosis and is almost a universal finding in patients with NASH. Results of pilot trials investigating the use of insulin-sensitizing agents not only in diabetic patients but also in nondiabetic patients have recently been published. Metformin,[28] thiazolidinediones,[29] and IKK [I-kappaB kinase] inhibitors appear to show promise in this setting.
During this year's EASL meeting, more data supporting the concept of using insulin-sensitizing agents in NASH were presented. One such report, presented by Tahan and colleagues,[30] explored the effect of rosiglitazone, an oral antidiabetic agent, in a rat model of NASH. The study authors showed that short-term (only 4 weeks) use of rosiglitazone significantly attenuated liver inflammation and reduced ALT levels in the MCDD (methionine and choline-deficient diet) rat model of NASH.
In another study, 64 patients were randomized to receive either rosiglitazone 4 mg/day, metformin 1000 mg/day, or neither of these agents (ie, were followed by diet); the study authors presented an interim analysis of their results.[31] Rosiglitazone was found to improve ALT activities and insulin resistance (as determined by the HOMA-R [homeostasis model assessment of insulin resistance] formula) in patients with NASH after 3 months of therapy. Metformin was found to decrease serum AST levels, but did not affect insulin resistance or ALT levels. We now await the longer follow-up data for these patients and especially anticipate the results of liver rebiopsy after treatment.
Antioxidants
Antioxidants may represent an alternative approach for treating patients with severe NASH, as there is accumulating evidence supporting a role for oxidant stress in the pathogenesis of this disorder.[32] Recently, probucol, a lipid-lowering agent with strong antioxidant properties, was successfully explored in a first pilot trial conducted in patients with NASH.[33] Data from several other trials were presented during EASL 2003 that also suggested that antioxidants and vitamins C and E may be of benefit in NASH.
A study from Italy investigated the relation of diet to insulin resistance and liver disease in 25 nonobese, nondiabetic patients with NASH.[34] It is interesting to note that the study authors found a highly significant negative correlation between steatosis and intake of polyunsaturated fat, vitamin C, and vitamin E.
A group from Turkey investigated oxidative modification of low-density lipoprotein (ox LDL) immunohistochemically in liver tissues of patients with NASH.[35] Ox LDL was found to occur at high degrees in liver tissue samples taken from patients with various liver injuries due to NASH, chronic viral hepatitis, and alcoholic hepatitis -- thus providing indirect evidence that oxidative stress indeed is present in the liver of these patients.
Perlemuter and colleagues[36] from France investigated antioxidant enzyme activities (cytosolic and mitochondrial superoxide dismutases; glutathione peroxidase) in liver tissue from obese patients with NASH. They found these antioxidant enzymes to have higher activities in the liver, but not in plasma or erythrocytes. Therefore, oxidative stress may be particularly present in the liver, but not in other compartments in these patients studied.
Finally, in a pilot study from Ankara, Turkey, 16 patients with NASH were treated with vitamin E 400 mg/day.[37] Of note, the investigators found that vitamin E treatment improved biochemical (ALT, AST), histologic (steatosis, inflammation), and ultrasonographic parameters after 6 months of treatment. However, no improvement was achieved in fibrosis stage after this short-term treatment. Thus, additional studies including larger populations are needed to clarify the role of vitamin E in the treatment of patients with NASH.
Alternative Strategies
Additional alternative therapeutic options were summarized by Dr. Bugianesi[23] during the President's premeeting. Among the options discussed were N-acetylcysteine and antiendotoxin/cytokine therapies.[38] Anti-TNF-alpha antibodies have been used to treat severe alcoholic steatohepatitis, but thus far, there is no indication for the use of these drugs in patients with NASH outside the setting of clinical trials. Ursodeoxycholic acid (UDCA) may have antiapoptotic and immunomodulatory effects,[39] and it has been tested in several smaller trials of patients with NASH.[24] In this setting, UDCA was found to result in normalization of ALT levels and, in 1 study, to also lead to a reduction in the amount of intrahepatic fat. However, randomized controlled trials are also lacking for UDCA in NASH. Thus, no final recommendation regarding the utility of this drug in patients with NASH can be made at present.
Concluding Remarks
Our understanding of the pathogenetic mechanisms underlying NAFLD and NASH has increased significantly in recent years. Several new therapeutic options are on the horizon; however, randomized multicenter trials are still lacking for most of these agents. It is hoped that within the next few years we will have evidence-based treatment guidelines combining well-tolerated lifestyle modifications with new drugs to help prevent progression of fibrosis in patients with NAFLD
Medscape Gastroenterology 5(2), 2003. © 2003 Medscape
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