Obesity-Epidemiology, Health risks
We are amidst a pandemic of obesity. According to the World Health Organization (WHO), there are now over 1 billion overweight adults worldwide, including at least 300 million obese individuals . However, the traditional WHO definitions of overweight and obesity [body mass index (BMI) >25.0 kg/m2 and >30.0 kg/m2, respectively] are inappropriately high for Asians (for whom overweight and obesity are defined as BMI >23.0 kg/m2 and 25.0 kg/m2, respectively) . When these new criteria are applied, there is need for further revision of current figures: 1.7 billion overweight persons would be a conservative global estimate. This upward trend has been observed for more than 2 decades. Obesity rates have tripled since 1980 in North America, the United Kingdom, Eastern Europe, Australasia, China, the Pacific islands, and the Middle East. The rise in childhood obesity is also of great concern, with 10% of children being now classified as overweight or obese.
Obesity-related health risks have traditionally focused on cardiovascular disease, type 2 diabetes mellitus, hypertension, stroke, cancer, sleep apnea, arthritis, and adverse psychosocial effects. While it has been recognized for some time that overweight/obese individuals who imbibe excess alcohol or take drugs such as methotrexate or halothane were at increased risk of hepatotoxicity, the relationship between obesity and liver disease was largely unrecognized until the recognition of nonalcoholic fatty liver disease (NAFLD) as a distinct clinical entity and as the prime overweight/obesity-related liver disorder.
An overview of nonalcoholic fatty liver disease
Nonalcoholic fatty liver disease constitutes a spectrum of liver disease ranging from simple fat accumulation in the liver (steatosis) to fat with liver injury and/or hepatic fibrosis (nonalcoholic steatohepatitis, NASH) through to cirrhosis. By its very definition, it is critical to exclude significant alcohol ingestion because similar histologic appearances are described for both disorders. NAFLD is the most common cause of liver test abnormalities in most industrialized countries and an emerging player in many Asia-Pacific countries . While NAFLD can result from use of drugs such as amiodarone, weight-reducing operations such as jejunoileal bypass, and certain inherited diseases, the majority of NAFLD cases encountered in clinical practice lack evidence of these secondary diseases. Instead, a common theme is the presence of metabolic disorders such as obesity (especially central obesity), type 2 diabetes, and dyslipidemia . Likewise, NAFLD is frequently present in both overweight and obese persons. Liver biopsies from overweight persons (BMI >25 kg/m2) show features of septal fibrosis in 30% and cirrhosis in 11% . The prevalence of NAFLD and NASH also increases with the severity of obesity. In one study of 212 consecutive patients undergoing bariatric surgery, the prevalence of NAFLD was 93% ; of these a quarter had features of NASH and 9% had advanced liver fibrosis (bridging fibrosis or cirrhosis).
Of the several subgroups of NAFLD, hepatic steatosis is the most prevalent type. This is indeed fortunate, because long-term studies have shown that steatosis has a benign course . By contrast, the outcome of NASH is less predictable. Among patients with NASH, individuals with advanced liver fibrosis/cirrhosis are at risk of liver-related death. In one study, liver-related mortality (11%) after a decade of follow-up exceeded the background population mortality rates by over 1000-fold . We have also shown that once cirrhosis develops, the rate of development of complications and liver-related mortality is quite similar to that seen in patients with chronic hepatitis C-related cirrhosis . Therefore, although in general NAFLD is a benign disorder, subsets of patients can have an adverse outcome.
In this article, we examine the interaction of obesity-related liver disease (principally NAFLD and the underlying insulin resistance) with another widely prevalent liver disease, chronic hepatitis C (CHC). The NAFLD-CHC interaction is a good illustration of the nexus between a primarily metabolic disorder and a viral infection. We discuss the predominantly genotype-specific effects of obesity in relation to steatosis in CHC, examine the underlying mechanisms, and provide an overview of the association between steatosis and hepatic fibrosis. Next, we consider the adverse impact of the overweight/obese state on the effectiveness of antiviral treatment in CHC. In the final section, we provide an outline of the management of obesity and its application to patients with NAFLD and CHC.
Steatosis and Chronic hepatitis C infection
Although not always present, steatosis is recognized as one of the cardinal histologic features of chronic hepatitis C. One could easily conclude that the steatosis-chronic hepatitis C association is coincidental, representing convergence of two common disorders, since the prevalence of NAFLD and hepatitis C virus infection in the US population is 20% and 1.8%, respectively. However, 30% to 70% of liver biopsies in CHC patients show evidence of steatosis, suggesting that hepatic steatosis occurs more often (by a factor of 2.5) than would be expected by chance . It therefore raises the question of whether viral factors or viral-host interactions are critical to the development of steatosis in CHC. Like NAFLD, only a proportion of CHC patients have advanced liver disease; cirrhosis develops in 7% to 24%  and hepatocellular carcinoma develops at the rate of 1% to 4% per year. Therefore, similar to NAFLD, there is continuing interest in determinants of advanced CHC. Hence, studying the genesis of steatosis in CHC is more than an academic question. If steatosis is indeed a crucial determinant of progression to advanced liver fibrosis in CHC, it raises the hope that unraveling the pathophysiologic pathways involved could prevent progression to advanced CHC and offer an alternative strategy for managing nonresponders with advanced CHC.
Where does the fat come from? Host or Virus?
A series of elegant studies have examined this critical question. There is now general consensus that host- and virus-related factors operate differently in the pathogenesis of hepatic steatosis. In particular, clear genotype-specific differences have been identified. Broadly, in genotype 1 hepatitis C virus (HCV)-infected patients, the host fat mass (and the underlying insulin resistance) correlates with the extent of hepatic steatosis, whereas the virus itself is responsible for much of the fat accumulation in those infected with genotype 3 HCV.
Steatosis in genotype 1 chronic hepatitis C infection
In genotype 1-infected CHC patients, host factors hold the key to the development of intrahepatic steatosis [11,12]. Of these, the host body fat mass, as represented by the BMI, is a critical determinant of the extent of hepatic steatosis. Hourigan and colleagues showed a progressive rise in steatosis with increasing BMI . In their report, the mean BMI values corresponding with steatosis grades 1, 2, and 3 were 23.9, 26.5, and 28.4 kg/m2, respectively . Likewise, Adinolfi and colleagues observed a strong correlation between BMI and hepatic steatosis (r = 0.69, P <.001) . Of their 80 overweight or obese subjects with HCV genotype 1, 81% had steatosis. On the other hand, the majority (70%) of genotype 3a subjects with steatosis had normal weight . This study also examined the association between steatosis and fat distribution. They showed clearly that, in genotype 1 HCV-infected patients, the distribution of obesity (peripheral vs central) had a bearing on the development of hepatic steatosis. Centrally obese patients were more likely to have steatosis (93% vs 43%) than those with peripheral obesity alone .
Pathogenesis of steatosis and fibrosis in genotype 1 CHC
The association of steatosis with visceral obesity suggests that it is not the BMI per se but the underlying insulin resistance (IR) that is critical to the development of liver fat. It has been repeatedly demonstrated that visceral fat is much more metabolically active and is more closely associated with IR than subcutaneous fat. Supporting a role for IR in CHC, the prevalence of the insulin resistance syndrome (metabolic syndrome) was much higher in patients with concurrent CHC and NAFLD features (over 90%) as compared to those with CHC alone (37%) .
The pathway to steatosis in genotype 1 patients has its beginnings in the development of IR. Briefly, IR is characterized by an inability to suppress adipocyte lipolysis . The ensuing free fatty acid flux to the liver provides the substrate for hepatic lipogenesis. In addition to adipocyte-derived free fatty acids as substrate, de novo hepatic lipogenesis also contributes up to a quarter of the intrahepatic triglyceride content in patients with NAFLD .
Hyperinsulinemia-stimulated transcription factors mediate this process. Important among these transcription factors are sterol regulatory element-binding protein-1 (SREBP-1c) and carbohydrate response element-binding protein (ChREBP). While both can activate most of the enzymes involved in lipogenesis, the latter also stimulates expression of pyruvate kinase in the liver. This enzyme is a key regulatory enzyme in the glycolytic pathway, which provides substrates for lipogenesis . Hyperinsulinemia also contributes to impaired hepatic fatty acid oxidation and impaired lipid export. The sum total of these perturbations of lipid metabolism is hepatic triglyceride accumulation (steatosis). Although host factors underlie IR in patients with CHC genotype 1, the hepatitis C virus may also directly contribute through action on several different cellular pathways (e.g., TNF-α, STAT-3, and SOCS-3 signaling). This is discussed further by Bugianesi, above.
Before we examine the nexus between IR and fibrogenesis, it is important to address the question of whether IR is a result rather than a cause of hepatic fibrosis in chronic hepatitis C. This is particularly important in patients with HCV-related cirrhosis because cirrhosis per se is associated with IR. However, Hui and colleagues have demonstrated IR both in noncirrhotic HCV patients and in persons with minimal fibrosis, making this possibility less likely . Further, even CHC patients with no fibrosis had higher IR scores when compared with controls with primary biliary cirrhosis, most of whom had at least moderate fibrosis . Thus, IR appears to be an important determinant of hepatic fibrosis progression, particularly in patients with genotype 1 CHC infection. Moreover, there is also an incremental association of IR with hepatic fibrosis. The probability of moderate fibrosis (stages 2-4) at a homeostasis model assessment method (HOMA-IR) level of 1 is 45% but rises to 68% at a HOMA-IR level of 5 .
How IR influences hepatic fibrosis progression has yet to be unravelled. One possible mechanism involves the direct effects of hyperinsulinemia on hepatic stellate cells, the principal cell type involved in liver fibrogenesis. Both insulin and insulin-like growth factor (IGF-1) can facilitate proliferation and also induce collagen production in rat and human hepatic stellate cells . The demonstration of insulin receptors on hepatic stellate cells further supports a direct role for insulin. Another key link between insulin and hepatic fibrosis involves connective tissue growth factor (CTGF), a multifunctional, profibrogenic molecule with extracellular matrix-inducing properties . The latter were formerly ascribed to transforming growth factor-β (TGF-β) but the prevailing view is that CTGF is probably the downstream mediator of these TGF-β effects. CTGF is coexpressed with TGF-β in many fibrotic disorders of the skin (keloids, systemic sclerosis, Dupuytren's contracture) and CTGF mRNA and/or protein is overexpressed in fibrotic lung, kidney, and liver diseases. In the liver, CTGF mRNA and/or protein levels are correlated with the severity of liver fibrosis, irrespective of the etiology of the liver disease . Further, hepatic stellate cells incubated with insulin and glucose showed increased expression of CTGF mRNA and/or protein . Therefore, IR could induce hepatic fibrosis through CTGF expression. However, recent studies add a further level of complexity by implicating the hepatitis C virus directly in hepatic fibrogenesis [19-21]. For example, Shin and colleagues have shown increased expression of fibrosis-related molecules, including CTGF and TGF-β1, in cocultures of HepG2-HCV core protein with hepatic stellate cells .
Other adipokines, steatosis, and fibrosis in CHC
Adipokines such as leptin and adiponectin can influence insulin sensitivity. As discussed below, however, their relationship to hepatic steatosis and fibrosis in CHC is an open question. The adipocyte-derived plasma protein adiponectin is an attractive candidate for mediating hepatic steatosis and fibrosis in chronic hepatitis C. Serum levels of adiponectin correlate inversely with BMI and with insulin sensitivity. Hypoadiponectinemia is associated with progressive grades of hepatic steatosis in patients with nonalcoholic steatohepatitis . In mouse models, adiponectin has been shown to improve insulin sensitivity and to decrease hepatic and muscle triglyceride content . Adiponectin also attenuates liver fibrosis in the carbon tetrachloride model of experimental liver fibrosis . At the present time, adiponectin assessment in chronic hepatitis C has been limited to a few studies. An inverse relationship with steatosis was observed in one study , but reports are conflicting. Others have not documented such an association  or have found a gender-specific relationship (only in males) . To our knowledge, circulating adiponectin levels have not been correlated with the degree of liver fibrosis in humans .
Like adiponectin, leptin, a 16 kd adipocyte-derived protein, has pleiotropic effects ranging from satiety to immune regulation and modulation of insulin sensitivity. Obese individuals have high leptin levels due to leptin resistance. Therefore, leptin has been suggested as a possible obesity-steatosis and obesity-fibrosis link. Further, animal models support a role for leptin in augmenting profibrogenic responses. However, in human studies of NASH, circulating leptin levels correlate only with the severity of steatosis in some  but not other studies . Further, in contrast to animal studies, serum leptin does not correlate with the extent of hepatic fibrosis in humans [28,29]. With respect to chronic hepatitis C, the data linking leptin to steatosis and fibrosis are conflicting. Leptin was found to be an independent predictor of liver steatosis  and liver fibrosis in chronic hepatitis C , but others have not observed such an association .
Steatosis in genotype 3 chronic hepatitis C infection
Although an early study showed that patients infected with genotype 3a had higher levels of steatosis than those with genotype 1, body weight and alcohol consumption were not included in the analysis . Rubbia-Brandt and colleagues have drawn our attention to the fact that, even after adjustment for BMI, moderate-to-severe steatosis is more often associated with genotype 3 CHC infection than with any other subtype . In their study, HCV genotype 3 patients comprised over 60% of those with moderate-to-severe steatosis. Similar findings were reported by Westin and colleagues . In their cohort, the highest grades of steatosis (>70% of hepatocytes affected) were found exclusively in genotype 3-infected persons .
Pathogenesis of steatosis and fibrosis in genotype 3 CHC
In contrast to genotype 1 infection, the hepatitis C virus itself is implicated in the development of steatosis in genotype 3-infected patients [12,34-36]. Several lines of evidence from clinical studies support this hypothesis. First, Kumar and colleagues demonstrated a reduction in hepatic steatosis in genotype 3 CHC patients achieving a sustained viral response: 71% showed complete reversal of steatosis and 14% had a reduction in steatosis by one grade . Further, viral relapse was followed by recrudescence of steatosis. A reduction in hepatic fat content was not observed for persons with genotype 1, irrespective of whether a sustained viral response (SVR) was achieved, or for genotype 3 nonresponders . This is consistent with a role for the virus in the pathogenesis of hepatic steatosis in this subgroup ("no virus, no fat"). Indeed, multivariate analysis showed that an SVR was the only factor associated with steatosis reversal. These results were confirmed in a large multicenter international study by Poynard and colleagues . Among those achieving SVR in their cohort, reduced steatosis in 77% (by at least 1 grade) and disappearance of steatosis in close to half (46%) were observed in patients infected with HCV genotype 3; the corresponding figures for nongenotype-3 sustained viral responders were 46% and 29%, respectively . The next thread of evidence linking the virus to steatosis in genotype 3-infected patients is the close correlation of HCV RNA titres in the serum (r = 0.79, P <.001), and of intrahepatic core protein expression with the degree of steatosis in CHC genotype 3 (but not genotype 1) . Finally, steatosis is a feature of transgenic mouse models expressing HCV core protein alone or in combination with other nonstructural proteins (e.g., NS5A). This subject is explored in detail by Koike . In brief, several HCV-associated proteins promote steatosis by mitochondrial membrane disruption, impairment of the microsomal triglyceride transfer protein (MTTP), and interactions with other cellular components involved in lipid flux such as apolipoprotein B. Because earlier studies used genotype-1-derived constructs, the genotype-specific association with steatosis was less clear-cut. However, a recent in vitro model expressing the HCV core protein of several different genotypes has been reported .
Association of fibrosis with steatosis in chronic hepatitis C
There is growing evidence that hepatic steatosis is associated with hepatic fibrosis. Patients with higher grades of steatosis have more advanced degrees of fibrosis. Although this is not a uniform finding, the majority (8 of 11 studies) have endorsed this observation . The mechanism(s) are unclear but are probably related to hepatic stellate cell activation consequent to lipid peroxidation occurring in steatotic livers. Chronic hepatitis C is also associated with lipid peroxidation and oxidative stress . Together, this could lead to an amplified necroinflammatory response, culminating in advanced liver fibrosis. Recent studies have drawn our attention away from steatosis as the major link to the fibrosis and instead have focused on the profibrogenic effects of the underlying IR (see above).
Adverse impact of steatosis, obesity, and IR on antiviral therapy
We first examine the association of hepatic steatosis with the rates of SVR and early viral response (EVR) to therapy. We then consider the effects of obesity and IR on SVR.
SVR and EVR rates are lower in patients with hepatic steatosis [37,41]. This is particularly true of persons with non-3 genotypes. In one study, genotype 1 (but not genotype 3) CHC patients achieving EVR were more likely (71% vs 42%) to have grade 0 steatosis (defined as 0% to 2% of hepatocytes with fat) than those who failed to achieve an EVR . The percentage of fat content remained an independent predictor of EVR, even after adjustment for age, gender, and BMI. The impact of steatosis on SVRs is illustrated in the study by Poynard and colleagues . They observed a marked difference in SVR between patients with and without steatosis (35% vs 57%, respectively; P <.001) for those carrying genotypes 1, 4, 5, and 6. Once again, this association persisted after adjustment for factors known to influence treatment response: age, gender, BMI, viral load, glucose, and fibrosis. Genotype 2-infected patients, who have generally high rates of SVR, also showed differences in SVR with respect to the presence or absence of steatosis (86% vs 96%, P = .04, respectively). Interestingly, in this large study, the degree of steatosis did not influence SVR rates for genotype 3-infected patients with and without steatosis (85% vs 76%, P = 0.34) .
In one of the few studies directly addressing this question, Bressler and colleagues showed that their subgroup of obese subjects with CHC receiving standard interferon or interferon-ribavirin had substantially lower SVR rates (odds ratio, 0.23) when compared to overweight or normal-weight individuals . Other reports have not directly examined the effect of BMI/obesity on SVR but first show lower rates in patients with steatosis, and then show a correlation between steatosis and BMI. As an example, in one Greek cohort, lower SVRs were observed in persons with any degree of steatosis on the index liver biopsy when compared with those without steatosis (39% vs 66%, P = .009) . Obesity was not selected as a variable associated with SVR but was indirectly implicated because steatosis correlated significantly with a BMI >25 kg/m2. However, it appears that it is not the obesity, nor the steatosis, but rather the associated IR that should be examined as one of the determinants of SVR. The study cited above did not specifically measure IR.
The importance of IR to SVRs is brought out in the report by Romero-Gomez and colleagues . In this Spanish study, IR was measured by the homeostasis model assessment method (HOMA), which involves measuring the product of serum insulin and glucose. HOMA-IR correlates well with the gold standard for assessing IR, the euglycemic clamp technique. IR was defined as a HOMA-IR >2. By multivariate analysis, IR, fibrosis, and genotype were independent predictors of SVR. As expected, BMI was a predictor of IR (odds ratio, 2.49), but when the multivariate analysis was performed including BMI, hepatic steatosis grade, and other variables, it was IR which was selected as an independent predictor. This does not prove causality but underscores the notion that IR is more critical than BMI as a determinant of treatment response. It is noteworthy that IR is a feature of difficult-to-treat patient cohorts: overweight individuals, African Americans, those with cirrhosis, and those coinfected with human immunodeficiency virus. Genotype-specific associations with IR are also brought out well in this report. SVR for genotype 1-infected patients showed a linear relationship with the measured HOMA-IR, with rates of 61%, 40% and 20% corresponding to HOMA-IR values of <2, 2 to 4, and >4 .
Mechanisms for low SVR in obese patients
Why SVR rates are low in obese patients is unclear. A number of different mechanisms have been discussed in a recent editorial . These relate to reduced bioavailability of interferon in obese subjects, the impact of obesity-related hepatic steatosis, which could potentially decrease drug-hepatocyte membrane contact, and immune dysregulation mediated by obesity-related leptin resistance. Higher fibrosis stage associated with higher grades of steatosis may also have a negative impact on the SVR. Some of these issues have been addressed in recent therapeutic trials, and weight-based dosing of ribavirin and pegylated interferon-alfa 2b is common. The impact of higher pegylated interferon and ribavirin doses is currently being explored.
Among more recent hypotheses is the role of obesity-related cytokines in impairing SVR. One such signaling molecule is suppressor of cytokine signaling 3 (SOCS-3), which is known to interfere with interferon-induced cellular signaling and to contribute to impaired antiviral responses . Increased levels of hepatic SOCS-3 expression were observed in obese genotype 1 CHC-infected patients. Further, genotype 1 nonresponders had higher levels of hepatic SOCS-3 protein expression than responders to antiviral treatment (46). SOCS-3 expression remained significant after correction for other factors associated with nonresponse to treatment. Interestingly, there were no significant differences in hepatic SOCS-3 expression between nonresponders and responders in CHC genotype 3-infected patients. SOCS-3 expression is strongly correlated with levels of IR-associated cytokines (e.g., TNF-α). This study lends further support to the hypothesis that IR is closely associated with steatosis in genotype 1 CHC cases.
Currently SVR rates, even with standard-of-care regimes (pegylated interferon with ribavirin), are suboptimal, especially in CHC genotype 1 patients. Therefore, there has been interest in seeking alternative treatment strategies in managing nonresponders to antiviral treatment. Given that IR underlies steatosis and fibrosis progression in chronic hepatitis C, it is logical to explore treatment approaches that improve IR. These include achieving body weight reduction and the use of pharmacotherapies to reduce IR.
Weight reduction strategies
The composite management of obesity involves behavioral treatment and adjunctive pharmacological and/or surgical measures. Short-term weight loss can be achieved by behavioral treatment approaches . These involve encouraging obese individuals to modify the eating, exercise, and thinking habits that contribute to weight gain. Multiple components are involved, with particular emphasis on maintaining records of food intake, an important determinant of short- and long-term weight loss. The objective of 10% weight loss is achieved within 6 months, but weight regain is a major problem. Up to one-third regain their weight rapidly within a year and most revert to their previous weight within 5 years . Ongoing physical activity and continued interaction with a dietician/health practitioner are critical in order to maintain weight after the initial successful weight reduction. Further, as shown in the diabetes prevention program study, despite lack of weight loss, as little as 4 hours of exercise per week improved metabolic profiles .
According to the National Institutes of Health guidelines, pharmacotherapy is indicated for patients with a BMI exceeding 30 kg/m2 alone or 27 kg/m2 or more with an obesity-related comorbid condition. Widely used among the drugs approved for long-term use are sibutramine, a serotonin and norepinephrine uptake inhibitor, and orlistat, a gastric and pancreatic lipase inhibitor. The former facilitates satiety, whereas the latter promotes mild fat malabsorption. While both drugs do assist in achieving loss of up to 8% to 10% of baseline body weight at 2 years, weight regain is a problem when the drugs are discontinued. Although these drugs are generally well tolerated, sibutramine is contraindicated in patients with cardiovascular disease or uncontrolled hypertension.
For persons with morbid obesity who have failed behavioral and drug therapy, bariatric surgery is the only option. Currently, bariatric surgery is approved only for persons with a BMI of 35 kg/m2 or more with an obesity-related disorder and for those with BMIs over 40 kg/m2 alone. Preferred surgical methods include gastric bypass (Roux-en-Y), gastric banding, vertical banded gastroplasty, and biliopancreatic diversion. A meta-analysis of 147 studies of obesity surgery concluded that surgery was more effective than nonsurgical methods for patients with morbid obesity (BMI >40 kg/m2), but more data were necessary for patients with lesser degrees of obesity. The overall mortality was less than 1%, with morbidity rates of around 20% . Therefore, bariatric surgery should be viewed as part of a multidisciplinary approach to combating the pandemic of obesity.
Impact on NAFLD
In the context of NAFLD, diet and exercise protocols can facilitate improvements in hepatic steatosis and necroinflammation. Effects on hepatic fibrosis are less robust, but this may be related to the short duration of the reported studies. Previously, weight loss of around 10% of baseline body weight was shown to improve the degree of steatohepatitis . However, a more recent study suggests that achieving a 5% reduction in body weight can improve serum transaminases and the metabolic profile . Although many drugs, including vitamin E and ursodeoxycholic acid, improve serum transaminases in NASH, no convincing effects on liver histology have been demonstrated. Most promising among the current drugs are drugs that improve insulin sensitivity such as metformin and the second generation thiazolidinediones. In a study of 55 patients, Bugianesi and colleagues showed that metformin 2 g daily for 12 months was better than vitamin E or a prescriptive diet . Of the 17 patients who underwent a follow-up liver biopsy, 10 showed improvement in steatohepatitis or hepatic fibrosis (by 1 grade), there was no change in 6 cases, and a deterioration in 1 patient. The thiazolidinediones, a new class of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, also improve insulin sensitivity. Troglitazone, the first of this class of drugs, improved liver histology in NAFLD but was withdrawn due to its hepatotoxic potential. The second generation thiazolidinediones, rosiglitazone and pioglitazone, are largely free of hepatotoxicity . Use of both rosiglitazone and pioglitazone has been associated with improvements in steatohepatitis grade and a reduction in the extent of zone 3 hepatic fibrosis. However, problems that need to be addressed with this class of agent include weight gain during treatment and the absence of sustained benefits after drug cessation. For the morbidly obese patient with NAFLD, accruing data confirm the beneficial effects of bariatric surgery. In one recent series, salutary effects on metabolic risk factors were demonstrated. The prevalence of the metabolic syndrome was reduced from 70% to 14% . Pronounced positive effects on liver histology were also observed in this series, with reduction in the frequencies of steatosis (88% to 8%), necroinflammation (from 23% to 2%), and fibrosis stage (from 31% to 13%). It is noteworthy that complete resolution of hepatic necroinflammation and steatosis was observed in 37% and 20% of patients, respectively.
Improving insulin sensitivity in patients with chronic hepatitis C
Pharmacological methods to reduce IR and bariatric surgical techniques have yet to be explored in patients with chronic hepatitis C. A pilot study showed that lifestyle interventions to improve insulin sensitivity are an emerging option for such patients. In this report from Queensland, Australia, 19 patients were commenced on a 3-month weight reduction diet and exercise schedule . Mean weight loss achieved was 5.9 kg (SD, 3.2). Paired pre- and post-treatment liver biopsies were available for 10 patients. Comparisons were made for fat content, inflammation, fibrosis scores, and the degree of staining for alfa-smooth muscle actin (a marker of stellate cell activation). An improvement in ALT was observed in 16; mean ALT at weeks 0 and 12 was 137 IU and 94 IU, respectively (P = .002). A reduction in steatosis was observed in 9 of the 10 paired liver biopsies, irrespective of genotype (5 patients had genotype 3, 4 had genotype 1). This correlated well with the degree of weight loss (r = 0.81). Even small reductions in body weight (2.6%) were associated with improvements in steatosis in some cases. More importantly, a decline in stellate cell activation along with a reduction in fibrosis was observed in 5 of the 9 subjects with a reduction in hepatic steatosis. Although the improvement in fibrosis could be attributed to a reduction in liver fat, it is noteworthy that insulin levels and the HOMA-IR (a marker of IR) were also decreased after treatment.
From a practical perspective, achieving and maintaining weight reduction requires a high level of motivation from the patient and the services of a dedicated therapist with expertise in lifestyle interventions (behavior modification, dietetics, and exercise physiology). In the study cited above, 3 of 8 patients completing 6-month follow-up had already regained over 25% of their lost weight. It is important to note that the benefits of weight reduction were also extended to genotype 3 patients. This suggests that even in this subgroup, host factors may contribute and that genotype-specificity for steatosis may not be absolute. Finally, the improvement in hepatic fibrosis stage (even at 12 weeks) is noteworthy. However, the impact of a longer intervention should be examined, not least with regard to adherence to the intervention.
1. Haslam DW, James WP. Obesity. Lancet 2005;366:1197-1209. [Medline]
2. Chitturi S, Farrell GC, George J. Non-alcoholic steatohepatitis in the Asia-Pacific region: future shock? J Gastroenterol Hepatol 2004;19:368-374. [Medline]
3. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221-1231. [Medline]
4. Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology 2000;118:1117-1123. [Medline]
5. Ong JP, Elariny H, Collantes R, et al. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg 2005;15:310-315. [Medline]
6. Dam-Larsen S, Franzmann M, Andersen IB, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 2004;53:750-755. [Medline]
7. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116:1413-1419. [Medline]
8. Hui JM, Kench JG, Chitturi S, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 2003;38:420-427. [Medline]
9. Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004;126:586-597. [Medline]
10. Freeman AJ, Dore GJ, Law MG, et al. Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology 2001;34:809-816. [Medline]
11. Hourigan LF, MacDonald GA, Purie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999;29:1215-1219. [Medline]
12. Adinolfi LE, Gambardella M, Adreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001;33:1358-1364. [Medline]
13. Sanyal AJ, Contos MJ, Sterling RK, et al. Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. Am J Gastroenterol 2003;98:2064-2071. [Medline]
14. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004;114:147-152. [Medline]
15. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005;115:1343-1351. [Medline]
16. Hui JM, Sud A, Farrell GC, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 2003;125:1695-1704. [Medline]
17. Rachfal AW, Brigstock DR. Connective tissue growth factor (CTGF/CCN2) in hepatic fibrosis. Hepatol Res 2003;26:1-9. [Medline]
18. Paradis V, Perlemuter G, Bonvoust F, et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 2001;34:738-744. [Medline]
19. Shin JY, Hur W, Wang JS, et al. HCV core protein promotes liver fibrogenesis via up-regulation of CTGF with TGF-beta1. Exp Mol Med 2005;37:138-145. [Medline]
20. Mazzocca A, Sciammetta SC, Carloni V, et al. Binding of hepatitis C virus envelope protein E2 to CD81 up-regulates matrix metalloproteinase-2 in human hepatic stellate cells. J Biol Chem 2005;280:11329-11339. [Medline]
21. Schulze-Krebs A, Preimel D, Popov Y, et al. Hepatitis C virus-replicating hepatocytes induce fibrogenic activation of hepatic stellate cells. Gastroenterology 2005;129:246-258. [Medline]
22. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 2004;40:46-54. [Medline]
23. Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001;7:941-946. [Medline]
24. Kamada Y, Tamura S, Kiso S, et al. Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology 2003;125:1796-1807. [Medline]
25. Petit JM, Minello A, Jooste V, et al. Decreased plasma adiponectin concentrations are closely related to steatosis in hepatitis C virus-infected patients. J Clin Endocrinol Metab 2005;90:2240-2243. [Medline]
26. Liu CJ, Chen PJ, Jeng YM, et al. Serum adiponectin correlates with viral characteristics but not histologic features in patients with chronic hepatitis C. J Hepatol 2005;43:235-242. [Medline]
27. Jonsson JR, Moschen AR, Hickman IJ, et al. Adiponectin and its receptors in patients with chronic hepatitis C. J Hepatol 2005;43:929-936. [Medline]
28. Chitturi S, Farrell G, Frost L, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology 2002;36:403-409. [Medline]
29. Chalasani N, Crabb DW, Cummings OW, et al. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? Am J Gastroenterol 2003;98:2771-2776. [Medline]
30. Romero-Gomez M, Castellano-Megias VM, Grande L, et al. Serum leptin levels correlate with hepatic steatosis in chronic hepatitis C. Am J Gastroenterol 2003;98:1135-1141. [Medline]
31. Piche T, Vandenbos F, Abakar-Mahamat A, et al. The severity of liver fibrosis is associated with high leptin levels in chronic hepatitis C. J Viral Hepat 2004;11:91-96. [Medline]
32. Muzzi A, Leandro G, Rubbia-Brandt L, et al; Swiss Hepatitis C Cohort Study. Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients. J Hepatol 2005;42:41-46. [Medline]
33. Mihm S, Fayyazi A, Hartmann H, Ramadori G. Analysis of histopathological manifestations of chronic hepatitis C virus infection with respect to virus genotype. Hepatology 1997;25:735-739. [Medline]
34. Rubbia-Brandt L, Quadri R, Abid K, et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol 2000;33:106-115. [Medline]
35. Westin J, Nordlinder H, Lagging M, Norkrans G, Wejstal R. Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients. J Hepatol 2002;37:837-842. [Medline]
36. Kumar D, Farrell GC, Fung C, George J. Hepatitis C virus genotype 3 is cytopathic to hepatocytes. Genotype-specific reversal of hepatic steatosis after sustained response to antiviral therapy. Hepatology 2002;36:1266-1272. [Medline]
37. Poynard T, Ratziu V, McHutchinson J, et al. Effect of treatment with Peginterferon or Interferon alpha-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 2003;38:75-85. [Medline]
38. Koike K. Hepatitis C as a metabolic disease: Implication for the pathogenesis of NASH. Hepatol Res 2005 [in press]. [Medline]
39. Abid K, Pazienza V, de Gottardi A, et al. An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation. J Hepatol 2005;42:744-751. [Medline]
40. Asselah T, Boyer N, Marcellin P. Steatosis in hepatitis C: what does it mean? Current Hepatitis Reports 2003;2:137-144.
41. Patton HM, Patel K, Behling C, et al. The impact of steatosis on disease progression and early and sustained viral response in chronic hepatitis C patients. J Hepatol 2004;40:484-490. [Medline]
42. Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 2003;38:639-644. [Medline]
43. Thomopoulos KC, Theocharis GJ, Tsamantas AC, et al. Liver steatosis is an independent risk factor for treatment failure in patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 2005;17:149-153. [Medline]
44. Romero-Gomez M, Del Mar Viloria M, Andrade RJ, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology 2005;128:636-641. [Medline]
45. McCullough AJ. Obesity and its nurturing effect on hepatitis C. Hepatology 2003;38:557-559. [Medline]
46. Walsh MJ, Jonsson JR, Richardson MM, et al. Non-response to antiviral therapy is associated with obesity and increased hepatic expression of SOCS-3 in patients with chronic hepatitis C, viral genotype 1. Gut 2006;55:529-535. [Medline]
47. Foster GD. Principles and practices in the management of obesity. Am J Respir Crit Care Med 2003;168:274-280. [Medline]
48. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. [Medline]
49. Maggard MA, Shugarman LR, Suttorp M, et al. Meta-analysis: surgical treatment of obesity. Ann Intern Med 2005;142:547-559. [Medline]
50. Suzuki A, Lindor K, Saver JS, et al. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J Hepatol 2005;43:1060-1066. [Medline]
51. 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. [Medline]
52. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003;38:1008-1017. [Medline]
53. Clark JM, Alkhuraishi AR, Solga SF, Alli P, Diehl AM, Magnuson TH. Roux-en-Y gastric bypass improves liver histology in patients with non-alcoholic fatty liver disease. Obes Res 2005;13:1180-1186. [Medline]
54. Hickman JJ, Clouston AD, MacDonald GA, et al. Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C. Gut 2002;51:89-94. [Medline]