Beyond insulin resistance: Innate immunity in nonalcoholic steatohepatitis

Obesity is an inflammatory disorder characterized by heightened activity of the innate immune system. Innate immune activation is central to the development of obesity-related insulin resistance; it also plays an important role in obesity-related tissue damage, such as that seen in atherosclerosis. Recent research has implicated the innate immune system in the pathophysiology of obesity-related liver disease. This review summarizes how innate immune processes, occurring both within and outside the liver, cause not only insulin resistance but also end-organ damage in the form of nonalcoholic fatty liver disease.     

Hypolactasia is associated with insulin resistance in nonalcoholic steatohepatitis

AIM To assess lactase gene(LCT)-13910CT polymorphisms in Brazilian non-alcoholic fatty liver disease(NAFLD) and nonalcoholic steatohepatitis(NASH) patients in comparison with healthy controls.METHODS This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, S?o Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence(LCT-13910CT) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients(steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher's exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed.RESULTS No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients(66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls(59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism(LCT-13910CT) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase nonpersistence(low lactase activity or hypolactasia) phenotype was associated with higher insulin levels(23.47 ± 15.94 μU/m L vs 15.8 ± 8.33 μU/m L, P = 0.027) and a higher frequency of insulin resistance(91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes(P = 0.651), dyslipidaemia(P = 0.328), hypertension(P = 0.507) or liver histology in these patients. Moreover, in the NASH patients, hypolactasia was an independent risk factor for insulin resistance even after adjusting for gender and age [OR = 5.0(95%CI: 1.35-20; P = 0.017)].CONCLUSION The LCT-13910 genotype distribution in Brazilian NAFLD patients was the same as that of the general population, but hypolactasia increased the risk of insulin resistance in the NASH patients.     

Interaction of iron,insulin resistance,and nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) has emerged as a ubiquitous liver disorder with occasional serious overtones. Although diabetes and obesity were initially held culpable, insulin resistance (IR) is now considered the fundamental operative mechanism. IR is probably the "first step" in nonalcoholic steatohepatitis (NASH). Oxidative stress may be the elusive "second" of possibly multiple steps in the progression of steatosis to fibrosing steatohepatitis. Because hepatic iron promotes oxidative stress, it was mooted as a contributory cofactor in NASH. This proposal was strengthened by an association with hepatic fibrosis. Subsequent studies have shown neither a significant increase in hepatic iron nor an association between hepatic iron and any of the histologic determinants in NASH. Likewise, the increased prevalence of hemochromatosis gene (HFE) mutations in some studies appears to be largely irrelevant to the development of hepatic fibrosis. Excess hepatic iron may occur in insulin resistance-associated iron overload (IRHIO), characterized by hyperferritinemia with normal to mild increases in transferrin saturation. Although patients with IRHIO have a high prevalence of IR-related metabolic disorders, the relationship of IRHIO to NASH is unclear. A recent study showed improvement in insulin sensitivity with the use of venesection in patients with NAFLD, but this approach cannot be implemented without extensive review.     

Relationship between altered postprandial lipemia and insulin resistance in normolipidemic and normoglucose tolerant obese patients

OBJECTIVE: Although there are changes in the postprandial lipid responses of obese patients, these are closely associated with high fasting triglycerides (TG). This study of 17 normotriglyceridemic, normoglucose-tolerant android obese subjects (body mass index, BMI = 34.3 +/- 3.1 kg/m2) and 33 normal-weight controls (BMI = 21.8 +/- 1.6 kg/m2) was done to examine their postprandial responses to an oral fat loading test containing retinol (890 calories, 85% fat) and to evaluate the possible association between clinical and biological features of obesity and/or insulin resistance and postprandial lipemia. SUBJECTS AND MEASUREMENTS: Blood samples were taken before giving the fat load and at 2,3,4,5,6 and 8 h after it. Insulin sensitivity was assessed using HOMA, and TG and retinyl palmitate (RP) in the plasma, chylomicrons and non-chylomicron fractions were measured each time. RESULTS: The areas under the curves (AUC) of chylomicron TG for the obese and controls were not different, indicating adequate lipolytic activity. By contrast, the AUC for non-chylomicron TG was significantly greater in the obese than in the controls (512 +/- 135 vs 429 +/- 141 mmol/lmin, P < 0.01). In addition, the AUC for RP in this same fraction was significantly lower in the obese than in the controls (103 +/- 55 vs 157 +/- 88 mg/l min, P < 0.05), suggesting that the TG from endogenous lipoproteins accounted for most of the increase in TG in the non chylomicron fraction. Parameters related to obesity showed no relationship with these postprandial abnormalities, whereas HOMA, which discriminated between the groups, partly explained (r2= 23%, P < 0.01) the significant increase in non-chylomicron TG. CONCLUSIONS: Android obese patients with a fasting TG in the normal range and not different from the fasting TG of lean controls had an abnormal postprandial lipemia response, indicated by a significantly greater TG in the non-chylomicron subfraction than in controls. These alterations may be partly due to postprandial changes in endogenous lipoproteins as a consequence of insulin resistance.     

Metabolic and anthropometric evaluation of insulin resistance in nondiabetic patients with nonalcoholic steatohepatitis

OBJECTIVES: Insulin resistance is nearly universal in patients with nonalcoholic steatohepatitis (NASH) when tested by glucose tolerance tests or clamp methods. However, the pattern of insulin resistance in these patients after a physiological challenge is unknown. We conducted a study to characterize the metabolic response to a mixed meal in nondiabetic patients with NASH (NDN) and to identify anthropometric determinants of insulin resistance in these patients. METHODS: Serum insulin, C-peptide, glucose, and free fatty acid (FFA) levels were measured at 0, 30, 60, 90, and 120 min after a 500-kcal standard meal in 18 NDN and 18 age-, gender-, and body mass index (BMI)-matched controls. Correlations were made between insulin resistance and various anthropometric, calorimetric, and serological variables. RESULTS: Compared with controls, NDN had significantly higher levels of insulin and C-peptide at baseline and after the mixed meal. However, glucose levels were not different either at baseline or after the meal. NDN had higher fasting levels of FFA than the controls (459 +/- 190 vs 339 +/- 144 micro mol/L, respectively, p = 0.03); however, meal-induced suppression in lipolysis was similar between the two groups (39 +/- 113% vs 46 +/- 60%, p = 0.8). Insulin resistance was significantly correlated with BMI (r = 0.39, p = 0.02) and visceral fat (r = 0.50, p = 0.004). Whereas BMI, percent total body fat, and subcutaneous abdominal fat were similar between the groups, the NASH group had significantly higher percent visceral fat compared with controls (28 +/- 10% vs 22 +/- 14%, p = 0.02). CONCLUSIONS: NDN are significantly hyperinsulinemic, both at fasting and after the mixed meal; however, their glucose homeostasis and suppression in lipolysis after a meal challenge are maintained. Insulin resistance in these patients is likely related to their higher visceral fat mass.     

清肝调脂饮对非酒精性脂肪性肝炎大鼠胰岛素抵抗的影响

目的探讨清肝调脂饮对非酒精性脂肪性肝炎（NASH）大鼠胰岛素抵抗的干预机制。方法建立高脂饲料诱导的Wistar大鼠NASH模型并随机分组,清肝调脂饮低、中、高剂量组和西利宾胺组分别灌胃相应剂量药物治疗。实验12周后,检测各组大鼠血清TG、TC、葡萄糖、瘦素、FFA、INS;肝组织行脂肪染色、糖原染色并作定量分析。结果与模型组比较,各用药组均能不同程度改善以上各指标（P〈0.05,P〈0.01）,其中,在降低TG、葡萄糖、INS、FFA方面,中药高剂量组均明显优于西药对照组（P〈0.05）。结论清肝调脂饮促进游离脂肪酸代谢与肝内TG分解;改善胰岛素抵抗（IR）及瘦素抵抗（LR）。与西利宾胺比较,清肝调脂饮在抑制NASH的IR方面具有明显的疗效优势。     

Endothelial function and postprandial lipemia

It is widely recognised that post-prandial lipoproteins play a role in the development of atherosclerosis, but the mechanisms underlying this role are unclear. An attractive working hypothesis is that the pathogenetic link is endothelial dysfunction. The available data seem to corroborate this theory and recognise triggering by oxidative stress, but some of the evidence is still contradictory.     

Dietary habits and behaviors associated with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD)is one of the most frequent causes of health problems in Western(industrialized)countries.Moreover,the incidence of infantile NAFLD is increasing,with some of these patients progressing to nonalcoholic steatohepatitis.These trends depend on dietary habits and life-style.In particular,overeating and its associated obesity affect the development of NAFLD.Nutritional problems in patients with NAFLD include excess intake of energy,carbohydrates,and lipids,and shortages of polyunsaturated fatty acids,vitamins,and minerals.Although nutritional therapeutic approaches are required for prophylaxis and treatment of NAFLD,continuous nutrition therapy is difficult for many patients because of their dietary habits and lifestyle,and because the motivation for treatment differs among patients.Thus,it is necessary to assess the nutritional background and to identify nutritional problems in each patient with NAFLD.When assessing dietary habits,it is important to individually evaluate those that are consumed excessively or insufficiently,as well as inappropriate eating behaviors.Successful nutrition therapy requires patient education,based on assessments of individual nutrients,and continuing the treatment.In this article,we update knowledge about NAFLD,review the important aspects of nutritional assessment targeting treatment success,and present some concrete nutritional care plans which can be applied generally.     

Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is a common but poorly understood liver disease. Our aim was to study a large group of patients referred for Hepatology consultation to further characterize this disorder, in particular its demographics and range of severity. We also sought to better understand its etiology and its relationship to the insulin resistance syndrome, known as the metabolic syndrome or syndrome X. METHODS: Retrospective review of 90 patients seen over a 4-yr period. RESULTS: Ninety patients aged 14-70 with NASH seen at the Liver Clinics at either the University of Tennessee or the Medical University of South Carolina. Eleven had complications of portal hypertension and seven of these had undergone or were awaiting transplantation. NASH was seen in nine families either in siblings or in subsequent generations. Diabetes or insulin resistance were present in almost all in this cohort of patients with NASH. Diabetes, hyperlipidemia, hypertension, and atherosclerotic disease, the components of syndrome X, were common in this population. CONCLUSION: NASH affects males and females equally, and presents over a wide age range. Despite its usually benign course, 28% of patients had cirrhosis and almost half of those had complications of portal hypertension, necessitating liver transplantation. Obesity was common in affected patients and cirrhosis was more common in the morbidly obese. Familial clustering was common, with 18% of patients having a similarly affected first degree relative. The clinical features that define syndrome X (diabetes, hypertension, hyperlipidemia, and atherosclerotic disease) are common in affected patients. Studies of glucose tolerance demonstrated unsuspected diabetes in six, and insulin resistance (the hallmark of syndrome X) in 85% of those tested. We hypothesize that NASH is a disorder of genetic etiology and is the hepatic manifestation of syndrome X, the insulin resistance syndrome.     

Therapeutic trials in nonalcoholic steatohepatitis: insulin sensitizers and related methodological issues

Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials.     

Alcoholic and nonalcoholic steatohepatitis

The constellation of histopathologic lesions that characterize alcoholic and nonalcoholic steatohepatitis has been well described and has served as the basis for clinical diagnosis, natural history studies, and experimental models for analyses of etiopathogenesis. The lesions common to both entities include, to varying degrees, steatosis, liver cell ballooning, lobular inflammation with a notable component of polymorphonuclear leukocytes, and a characteristic form of fibrosis that is initially located in the perisinusoidal regions of acinar zone 3. Cirrhosis with or without steatosis or steatohepatitis may occur in both entities. Mallory's hyaline is common but not necessary; megamitochondria and varying amounts of iron may be observed in either process. Hepatocellular carcinoma is a recognized complication of both processes, albeit with greater frequency in the former. Alcoholic hepatitis may present with more severe clinical and histologic manifestations than the nonalcoholic counterpart, including significant morbidity and mortality. The perivenular lesions collectively referred to as sclerosing hyaline necrosis are markers of severity, and are not common in nonalcoholics. In many instances, however, the microscopic lesions of these two processes are similar, likely as a reflection of common pathogenetic pathways, and the distinction between the two is ultimately clinically derived.     

Inflammation in nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) describes a range of disorders characterized by excess accumulation of triglyceride within the liver. While simple steatosis may be clinically stable, nonalcoholic steatohepatitis (NASH) can be progressive. Inflammation is believed to be the driving force behind NASH and the progression to fibrosis and subsequent cirrhosis. This article will review and interpret the current literature in an attempt to expand our understanding of the environmental and genetic causes of inflammation and its effects in NAFLD.