Advanced hepatic fibrosis and cirrhosis due to nonalcoholic fatty liver disease in Sri Lankan children: a preliminary report

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and may progress to advanced hepatic fibrosis and cirrhosis in some patients. Cirrhosis due to NAFLD is considered extremely rare in children in the Asia–Pacific region. We report the characteristics of 5 children with advanced hepatic fibrosis and cirrhosis due to NAFLD. Four of them were obese, and all of them had high alanine transaminase levels and ultrasonographic evidence of fatty liver. None had diabetes mellitus or hyperlipidemia. The calculated HOMA-IR was more than two in all five cases. Liver biopsy showed stage III fibrosis in 2 patients and stage IV fibrosis (cirrhosis) in 3.     

Orlistat Reverse Fatty Infiltration and Improves Hepatic Fibrosis in Obese Patients with Nonalcoholic Steatohepatitis (NASH)

Nonalcoholic steatohepatitis (NASH) may cause progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Treatment, thus far, has been restricted to diet and weight loss, but without compelling results. In this study we aimed to evaluate the efficacy of orlistat therapy in obese patients with NASH. Fourteen obese patients with NASH underwent liver biopsy prior to and subsequent to 6 months treatment with orlistat (120 mg tid). Hepatic fat extension was graded as normal, mild, moderate, or severe. Hepatic fibrosis was scored on a scale from 0 to 4, with 0 denoting no fibrosis and 4, cirrhosis. Portal inflammation was scored as 0-3, with 0 = normal, 1 = mild, 2 = moderate, and 3 = severe inflammation. Fourteen patients had NASH associated with diabetes, hyperlipidemia, or obesity. Orlistat reduced fatty infiltration in 10 patients (70%; P<0.01), 3 of whom had normal liver fat content after treatment. Orlistat improved inflammatory activity by 2 grades in 28% and by 1 grade in 50% of patients and effected no change in 22% of patients. Five patients (35%) returned to normal inflammatory activity. Orlistat improved hepatic fibrosis by 2 grades in three patients (21%) and by 1 grade in seven patients (50%). There was no change in four patients (28%). Orlistat lowered aminotransferases levels, total cholesterol, triglycerides and low-density lipoprotein, respectively. Insulin resistance index and malonyl dialdehyde levels improved significantly after orlistat therapy, whereas HbAic remained unchanged. In conclusion, in obese patients with NASH, liver fibrosis and inflammation improved after therapy with orlistat.     

Effects of weight loss surgeries on liver disease

Obesity is the single most significant risk factor for the development of nonalcoholic fatty liver disease (NAFLD) in children and adults. NALFD is estimated to occur in 30 to 100% of obese adults, and in approximately 53% of obese children. The majority of obese patients have ultrasonographic evidence of fatty liver; 30% have histologically documented nonalcoholic steatohepatitis (NASH). Up to 25% of patients with NASH may progress to cirrhosis. In the United States, an estimated 65% of adults are overweight and 31% are obese. Between 2001 and 2002, the number of people with severe obesity, who are more than 100 pounds overweight, rose to nearly 11 million. Since 1970, levels of childhood and teen overweight have climbed to approximately 16% in those aged 6 to 19 years. Recent findings indicate that key features of NAFLD and NASH improve or resolve dramatically with weight loss. This article discusses weight loss surgeries and their effects on liver disease.     

Pediatric fatty liver disease: Role of ethnicity and genetics

Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the most common form of liver disease in childhood as its prevalence has more than doubled over the past 20 years, paralleling the increased prevalence of childhood obesity. It currently affects between 3% and 11% of the pediatric population reaching the rate of 46% among overweight and obese children and adolescents. The prevalence of hepatic steatosis varies among different ethnic groups. The ethnic group with the highest prevalence is the Hispanic one followed by the Caucasian and the African-American. This evidence suggests that there is a strong genetic background in the predisposition to fatty liver. In fact, since 2008 several common gene variants have been implicated in the pathogenesis of fatty liver disease. The most important is probably the patatin like phospholipase containing domain 3 gene (PNPLA3) discovered by the Hobbs’ group in 2008. This article reviews the current knowledge regarding the role of ethnicity and genetics in pathogenesis of pediatric fatty liver.     

Is there any link between dietary pattern and development of nonalcoholic fatty liver disease in adolescence? An expert review

Evaluation of: Oddy WH, Herbison CE, Jacoby P et al. The western dietary pattern is prospectively associated with nonalcoholic fatty liver disease in adolescence. Am. J. Gastroenterol. 108, 778–785 (2013).

The prevalence of overweight and obesity in childhood is a major public health concern. According to the obesity trend, the prevalence of pediatric nonalcoholic fatty liver disease (NAFLD) is also increasing. Nonalcoholic fatty liver disease is characterized by a spectrum of hepatic lesions (i.e., steatosis, ballooning, necroinflammation and fibrosis) that can progress to cirrhosis, hepatocellular carcinoma and liver failure with the consequent need for liver transplantation. Pediatric NAFLD is typically of primary origin and it is strongly associated with several features of the metabolic syndrome such as obesity, insulin resistance, dyslipidemia and Type 2 diabetes. The evaluated article reports the prospective relationship between dietary patterns at age 14 years and the presence of NAFLD at age 17 years. A total of 995 adolescents completed a food frequency questionnaire at 14 years and had liver ultrasound at 17 years. Prospective associations between the dietary pattern scores and the risk of NAFLD were analyzed using multiple logistic regression analyses. Nonalcoholic fatty liver disease was present in 15.2% of adolescents. A healthy dietary pattern at 14 years appeared protective against NAFLD at 17 years in centrally obese adolescents. On the contrary, a western dietary pattern at 14 years in this cohort was associated with an increased risk of NAFLD at 17 years, particularly in obese adolescents.     

Steatohepatic cirrhosis in a morbidly obese patient

Sixty to ninety percent of obese subjects show histological abnormalities of the liver. The hepatic lesion can be classified into one of the four following groups: steatosis, steatohepatitis, fibrosis and cirrhosis. The incidence of cirrhosis among patients with fatty liver changes ranges from 1.5% to 8%. The now abandoned surgery procedures performed for the treatment of morbid obesity (jejunoileal bypass) had left a negative experience: the onset of acute hepatic failure in subjects with no previous hepatic disease or the development of cirrhosis within one year of the bypass. Very low formula diets leading to precipitous weight loss in morbidly obese people induce metabolic changes similar to those observed after jejunoileal bypass. We report the case of a morbidly obese patient who had lost 40 kg of weight during the 6 months previous to his hospitalization. He came with signs of hepatic failure. He worsened rapidly and died in a month-time. The hepatic tissue obtained post-mortem showed a non alcoholic steatohepatitic cirrhosis.     

血清HA、PCⅢ、CIV定量对肝组织纤维经诊断的意义

目的 探讨血清纤维化指标透明质酸（HA）、Ⅲ型前胶原（PCⅢ）、Ⅳ型胶原（CⅣ）定量对肝组织纤维化不同阶段诊断的临床应用价值。方法 用放射免疫法（RIA）检测253例慢性肝病患者血清HA、PCⅢ、CⅣ水平,所有患者同时做了肝组织活检。以病理诊断为金标准,采用ROC（Receiver Operating Curve)曲线确立HA、PCⅢ、CⅣ诊断肝纤维化（分期≥S2)和肝硬化（分期S4）的截断值及其诊断的灵敏度（Se)、特异度（Spe)、阳性预测值（PPV）和阴性预测值（NPV）。结果 血清HA、PCⅢ、CⅣ诊断肝纤维化（分期≥S2）的截断值分别为90μg/L、90μg/L、75μg/L,其诊断的灵敏度分别为80.4%、82.0%、63.1%,特异分别为70.2%、60.8%、83.8%,阳性预测值（PPV）分别为86.7%、83.5%、90.4%,阴性预测值（NPV）分别为59.8%、58.4%、48.4%。HA、PCⅢ、CⅣ诊断肝硬化的截断值分别分210μg/L、150μg/L、90μg/L,其诊断的灵敏度分别为96.2%、76.4%、80.0%,特异度分别为85.3%、68.7%、75.8%,PPV分别为65.4%、40.4%、47.8%,NPV分别为98.8%、91.3%、93.2%。结论 测定血清HA、PCⅢ、CⅣ水平可以肝纤维化不同阶段做出相对准确的诊断。其中以HA对肝梗化诊断的临床应用价值最大。     

Nonalcoholic fatty liver disease in severely obese subjects

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has been consistently associated with obesity and insulin resistance. Nonalcoholic steatohepatitis (NASH) is a histological entity within NAFLD that can progress to cirrhosis. The exact prevalence of NASH in severe obesity is unknown. It is unclear whether differences in insulin sensitivity exist among subjects with NASH and simple fatty liver. OBJECTIVE: To evaluate the prevalence and correlates of NASH and liver fibrosis in a racially diverse cohort of severely obese subjects. DESIGN: Ninety-seven subjects were enrolled. Liver biopsies, indirect markers of insulin resistance, metabolic parameters, and liver function tests were obtained. RESULTS: Thirty-six percent of subjects had NASH and 25% had fibrosis. No cirrhosis was diagnosed on histology. Markers of hyperglycemia, insulin resistance, and the metabolic syndrome but not body mass index were associated with the presence of NASH and fibrosis. Elevated transaminase levels correlated strongly with NASH and fibrosis but 46% subjects with NASH had normal transaminases. Subjects with NASH had more severe insulin resistance when compared to those with simple fatty liver. A signal detection model incorporating AST and the presence of diabetes predicted the presence of NASH while another incorporating ALT and HbA1C predicted the presence of fibrosis. CONCLUSIONS: NAFLD is associated with the metabolic syndrome rather than excess adipose tissue in severe obesity. Insulin resistance is higher in subjects with NASH versus those with simple fatty liver. Statistical models incorporating markers of liver injury and hyperglycemia may be useful in predicting the presence of liver pathology in this population.     

Clinicopathological Study of Alcoholic Fibrosis

Among 112 patients with alcoholic liver injury, 45 had alcoholic fibrosis. The incidence of alcoholic fibrosis was 40.2% which was the highest among various types of alcoholic liver injury (fatty liver: 3.6%, alcoholic hepatitis; 2.7% and liver cirrhosis: 31.3%). Clinical features of alcoholic fibrosis were milder than those of liver cirrhosis and more severe than those of fatty liver. The mean laboratory values in alcoholic fibrosis were significantly different from those in fatty liver and liver cirrhosis. The laboratory data were well correlated with the presence of pericellular fibrosis and thickening of the terminal hepatic venule, but only partially with hepatic cell necrosis and not with fatty metamorphosis. Two patients with alcoholic fibrosis who developed cirrhosis without any clinical and histological features of hepatitis were observed during 5-yr follow-up. These results indicate that alcoholic fibrosis is the most common type of alcoholic liver injury in Japan and is an independent clinicopathological entity distinct from the classical types of alcoholic liver injury. Pericellular fibrosis and thickening of the terminal hepatic venule which are the main histological features of alcoholic fibrosis may play an important role in its transition to liver cirrhosis.     

Liver pathology in morbidly obese patients with and without diabetes

The contribution of obesity and/or diabetes to liver pathology in the morbidly obese patient is controversial. We studied the liver biopsies of 100 consecutive patients undergoing gastric bypass surgery for morbid obesity. Multiple morphologic parameters were analyzed and graded independently, without knowledge of the clinical history, liver function tests, and oral glucose tolerance results of the patients. Six percent of the entire group demonstrated no fat, 42% mild fat, 20% moderate fat, and 24% severe fatty metamorphosis of the liver. Twenty-three percent of the patients had central vein fibrosis, 23% sinusoidal fibrosis, 19% bridging fibrosis, and 4% cirrhosis. Thirty-six percent of the patients had some degree of steatohepatitis, 66% possessed so-called glycogen nuclei of hepatocytes, 6% had PAS-positive thickening of blood vessels in the portal tracts, and 1% had lipogranulomas. The degree of fatty metamorphosis and fibrosis was analyzed in three separate groups, categorized by the glycemic status of the patient: 46 patients with normal glucose tolerance (NGT), 23 patients with impaired glucose tolerance (IGT), and 31 patients with non-insulin-dependent diabetes mellitus (NIDDM). Increasing severity of fatty metamorphosis from the normoglycemic obese to the diabetic obese patients was found, which was statistically significant by chi 2 analysis. Four of the six patients showing no fatty metamorphosis were normoglycemic. Glycogen nuclei and PAS-positive blood vessels were significantly more prevalent in the diabetic obese than in the normal obese. In conclusion, the distribution of significant liver histopathology in the morbidly obese patient correlates in severity with the degree of impaired glycemic status.     

高脂高糖、饮酒建立家兔脂肪肝模型及超声量化诊断

目的:模拟人类不良饮食结构建立家兔不同程度脂肪肝模型,进行肝脏背向散射积分 (integrated backscatter,IBS)和图像灰阶平均强度(gray scale,GS)测定,并结合临床研究,探讨具有病理基础的脂肪肝无创性超声量化诊断标准．方法:选用纯种新西兰家兔40只,采用高脂高糖饲料及乙醇饮料建立不同程度脂肪肝模型三组(每组n=10),设立对照组(n=10):临床病例同步进行肝组织病理学及超声检测．病理组织学检测采用苏丹Ⅳ,HE和Masson三色染色:应用HP Sonos 5500超声诊断仪实时检测肝脏IBS,包括图像平均强度(average image intensity,AII)、峰-峰强度及图像强度标准差; 采用Photo shop 7．0直方图分析超声图像GS．所得数据采用SAS8．2进行统计学分析．结果:肝脏AII随脂肪变加重呈递增趋势,正常肝<轻度脂肪肝<中度脂肪肝<重度脂肪肝,尤以近区各组间差异显著(P<0．0001);同等程度肝脂肪变AII随炎症的发生而增大．临床研究显示,IBS对脂肪肝诊断率及与病理组织学符合率(85．7％)较常规超声检测(57．1％) 明显增高,重度脂肪肝AII显著高于轻度脂肪肝(P<0．0001,0．001或0．05)．肝脏GS与AII相关,于肝左、右叶近区二者随病变加重呈一致性增高趋势(r1=0．442 21,P1=0．0012:r2= 0．335 73,P2=0．0160)．中重度脂肪肝伴炎症 GS显著高于正常肝及轻度脂肪肝(P<0．05)．结论:高营养及乙醇联合喂养家兔可快速建立不同程度脂肪性肝病模型;肝脏超声IBS及 GS强度可反映肝脂肪变、炎症和纤维化的病变程度,为脂肪肝无创性量化诊断提供可靠依据．     

Pathophysiological similarities and synergisms in alcoholic and non-alcoholic steatohepatitis

Chronic alcohol consumption is one of the main etiological factors for liver disease worldwide, however only a fraction of drinkers develop significant hepatic inflammation (alcoholic steatohepatitis), and even less progress to significant hepatic fibrosis and cirrhosis. The pathophysiological significance of hepatic lipid accumulation in the absence of significant alcohol consumption is also increasingly recognized. Non-alcoholic fatty liver disease (NAFLD) is regarded as the hepatic manifestation of the metabolic syndrome, and it is the most common cause of liver enzyme elevations in Western countries. Similarly to alcoholic liver disease, NAFLD encompasses mild hepatic steatosis to non-alcoholic steatohepatitis with significant necroinflammation and progressive fibrosis. Several clinical studies suggest a strong causative link between the consumption of alcohol and progressive liver disease in individuals with high fat intake and/or diabetes. However, it is incompletely understood how alcohol and obesity interact and whether the combined effects on the progression of liver injury are additive or synergistic. This review describes single as well as combined effects of alcohol and (components of) the metabolic syndrome on hepatic steatosis, inflammation and fibrosis. In addition to direct effects on the liver, the view is expanded to other organs affected by chronic alcohol consumption or the metabolic syndrome, to understand also extrahepatic pathophysiological mechanisms involved in hepatocellular injury. Undoubtedly, alcohol and the metabolic syndrome appear as a dangerous mix, and there are important synergistic effects of either condition with regard to crucial triggers of liver injury.     

Clinical significance of hepatic iron deposition and serum iron values in patients with chronic hepatitis C infection

OBJECTIVES: To assess the potential association between hepatic iron deposition or serum iron values and hepatic fibrosis and inflammatory activity in patients with chronic hepatitis C virus infection. METHODS: In 100 consecutive patients with hepatitis C virus infection, tissue iron deposition was assessed by quantifying iron stain on liver biopsy specimens. Serum iron, ferritin, and transferrin saturation were determined by standard laboratory procedures. Statistical analyses incorporated potential confounders associated with hepatic fibrosis. RESULTS: Twenty-one patients had no fibrosis (stage 0), 13 had portal fibrosis (stage 1), 31 had periportal fibrosis (stage II), 10 had bridging fibrosis (stage III), and 25 had cirrhosis (stage IV). Positive iron stain found in liver biopsy specimens of 19 patients was associated with stage III or IV fibrosis (p = 0.004). No significant difference was found between the iron concentration or the hepatic iron index in patients with stage III or IV fibrosis compared with patients with stage I or II fibrosis. At least 1 of 3 serum iron values assessed was abnormal in 55 patients. In univariate analysis, elevated serum iron (p = 0.01), serum ferritin (p < 0.001), and transferrin saturation (p = 0.002) were associated with stage III or IV fibrosis. In multivariate analysis, the only independent predictive factor of severe hepatic fibrosis was serum ferritin (p < 0.02; odds ratio = 11.35). The serum ferritin value and tissue iron stain had a significant positive correlation (p < 0.001). CONCLUSIONS: Increased hepatic iron deposition may be associated with more advanced hepatic fibrosis in patients with chronic hepatitis C virus infection. The serum ferritin value, an independent predictor of severe hepatic fibrosis in patients with chronic hepatitis C virus infection, may predict hepatic iron deposition and severity of fibrosis.     

Nonalcoholic fatty liver disease： An overview of current insights in pathogenesis, diagnosis and treatment

Estimates of people suffering from overweight （one billion） and obesity （300 million） are increasing. The accumulation of triglycerides in the liver, in the absence of excess alcohol intake, has been described in the early sixties. It was not until 1980, however, that Ludwig et al named this condition nonalcoholic steatohepatitis （NASH）. Subsequently, nonalcoholic fatty liver disease （NAFLD） has been used as a general name for conditions ranging from simple steatosis through steatohepatitis to end-stage liver disease （cirrhosis）. Many studies have demonstrated the significant correlation with obesity and insulin resistance. Other studies have revealed a signifi- cant correlation between hepatic steatosis, cardiovascu- lar disease and increased intima-media thickness. WHO estimated that at least two million patients will develop cirrhosis due to hepatic steatosis in the years to come. Longitudinal cohort studies have demonstrated that those patients with cirrhosis have a similar risk to devel- op hepatocellular carcinoma as those with other causes of cirrhosis. Taken all together, NAFLD has become the third most important indication for liver transplantation. There- fore, training programmes in internal medicine, gastroen- terology and hepatology should stress the importance of diagnosing this entity and treat properly those at risk for developing complications of portal hypertension and con- comittant cardiovascular disease. This review will focus on the clinical characteristics, pathophysiology, imaging tech- niques and the readily available therapeutic options.     

Hepatic histology in obese patients undergoing bariatric surgery

BACKGROUND/AIMS: Obesity is one of the most important clinical associations with non-alcoholic steatohepatitis (NASH). Our aim was to assess the prevalence of non-alcoholic fatty liver disease (NAFLD)/NASH in morbidly obese patients and the risk factors to more aggressive liver disease in this population. METHODS: Review of available studies on prevalence of NAFLD/NASH in severely obese patients submitted to bariatric surgery. RESULTS: Twelve observational and transversal studies were included, with consecutive recruitment, and prospective evaluation of data, summing 1620 patients with severe obesity. Prevalence of steatosis and NASH was 91% (range: 85-98%) and 37% (24-98%), respectively, with unexpected cirrhosis in 1.7% (1-7%). NASH was not related with age or body mass index, but there was an association between male sex and NASH/hepatic fibrosis. Diabetes mellitus and insulin resistance were the conditions most frequently associated with NASH, and hypertension with advanced hepatic fibrosis. CONCLUSIONS: There is a very high prevalence of NAFLD in asymptomatic morbidly obese patients, more than one-third presenting histological criteria for NASH. This review underscores the large variations in prevalence of NASH between studies, calling for the need for a better agreement in the use of the histological criteria.     

Joint effects of body weight and alcohol on elevated serum alanine aminotransferase in the United States population.

BACKGROUND & AIMS: Both alcohol and obesity are associated with hepatic steatosis. However, little is known about whether the toxicity of alcohol to the liver is influenced by adiposity. We examined the relationship of alcohol drinking and binge drinking with abnormal serum aminotransferase activity in normal weight, overweight, and obese persons in a national, population-based study. METHODS: Data were analyzed from 13,580 adult participants in the third US National Health and Nutrition Examination Survey, 1988-1994, after excluding participants with hepatitis B or C or iron overload. Abnormal aminotransferase levels were defined by using sex-specific cutoffs for ALT and AST. Analyses were adjusted for other liver injury risk factors. RESULTS: The prevalence of abnormal aminotransferase activity was elevated with consumption of >2 drinks per day or with overweight and obesity. In multivariate analysis, there was no association of alcohol intake with a higher prevalence of elevated aminotransferase levels among normal weight persons. In contrast, among overweight persons, consumption of >2 drinks per day increased the risk of elevated aminotransferase levels, and among the obese, > or = 1 drink per day was associated with a higher risk. Results were similar with elevated ALT alone as the outcome. With elevated AST alone as the outcome, intake of >2 drinks per day increased the risk, even among normal weight persons. Binge drinking was associated with aminotransferase elevation among obese consumers of 1-2 drinks per day. CONCLUSIONS: In this large, national, population-based study, overweight and obesity increased the risk of alcohol-related abnormal aminotransferase activity.     

Obesity is an important determinant of severity in newly defined metabolic dysfunction-associated fatty liver disease

BackgroundThe recently proposed definition of metabolic dysfunction-associated fatty liver disease (MAFLD) is based on the co-existence of hepatic steatosis with other metabolic disorders, including obesity and metabolic risk abnormalities such as hyperglycemia, high blood pressure and dyslipidemia. This study aimed to assess MAFLD severity according to the presence of metabolic abnormalities and obesity.MethodsUsing transient elastography, hepatic steatosis and fibrosis severity were assessed by measuring the controlled attenuation parameter and liver stiffness measurement. A total of 1163 patients with MAFLD were categorized into the following four groups according to metabolic risk abnormalities and obesity presence: non-obese without metabolic risk abnormality group (Group 1; reference group); non-obese with metabolic risk abnormality group (Group 2); obese without metabolic risk abnormality group (Group 3); and obese with metabolic risk abnormality group (Group 4). A multiple logistic regression analysis was performed to determine severe hepatic steatosis and fibrosis risk in each group in both unadjusted and adjusted models.ResultsIn the adjusted model, the odds ratios (ORs) [95% confidence interval (CI)] for severe hepatic steatosis in Groups 2, 3, and 4 were 1.07 (0.61-1.88), 2.43 (1.44-4.08), and 4.07 (2.56-6.48), respectively (P_trend < 0.001). For liver fibrosis, compared with Group 1, Group 2 showed no significant increases in OR, whereas Groups 3 and 4 (obese groups) showed significant increases (OR = 4.70, 95% CI: 1.24-17.82 and OR = 6.43, 95% CI: 1.88-22.02, respectively).ConclusionsObesity, rather than metabolic abnormality, is the principal determinant of severe hepatic steatosis and fibrosis in patients with MAFLD.     

Portal fibrosis and hepatic steatosis in morbidly obese subjects: A spectrum of nonalcoholic fatty liver disease

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can lead to hepatic fibrosis and cirrhosis. Portal fibrosis in the absence of NASH, called isolated portal fibrosis (IPF), has received less attention and has not been classified as a spectrum of NAFLD. The aims of this study were to determine the prevalence of IPF in subjects undergoing gastric bypass surgery, to identify biochemical variables associated with IPF, and to assess the metabolic syndrome as defined by the AdultTreatment Panel III criteria. We analyzed liver biopsies from 195 morbidly obese subjects after excluding all other causes of liver disease. The prevalence of fatty liver (FL) only, IPF, and NASH was 30.3%, 33.3%, and 36.4%, respectively. Several biochemical parameters significantly trended across the 3 groups, with IPF falling between FL and NASH. Hyperglycemia was the only metabolic parameter associated with NASH (OR, 5.4; 95% CI, 2.4-12; P < .0001) and IPF (OR, 2.8; 95% CI, 1.2-6.5; P = .01). Subjects with diabetes had the greatest risk for NASH (OR, 8; 95% CI, 3.3-19.7; P < .0001) and IPF (OR, 4.3; 95% CI, 1.6-11.6; P = .003). The metabolic syndrome was identified in 78.5% of subjects, and a significant trend for the number of metabolic criteria was observed across the spectrum of FL, IPF, and NASH. In conclusion, a significant subset of morbidly obese individuals has portal fibrosis in the absence of NASH that is associated with glycemic dysregulation. Therefore, IPF should be considered a spectrum of NAFLD that may prelude NASH in morbid obesity.     

Impact of Diabetes Mellitus and Insulin on Nonalcoholic Fatty Liver Disease in the Morbidly Obese

Introduction and aim. The prevalence of obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease are increasing. Type 2 diabetes mellitus may aggravate non-alcoholic fatty liver disease, increasing the risk of developing cirrhosis and hepatocellular carcinoma. This study aims to determine the effect of type 2 diabetes mellitus and insulin therapy on non-alcoholic fatty liver disease in the patients with morbid obesity. Material and methods. Clinical, anthropometric and laboratory data were analyzed together with intraoperative liver biopsies from morbidly obese patients undergoing bariatric surgery. Results. 219 patients with morbid obesity were evaluated. Systemic arterial hypertension (55.9% vs. 33.8%, p = 0.004) and dyslipidemia (67.1% vs. 39.0%, p < 0.001) were more prevalent in patients with diabetes when compared to patients without diabetes. In multivariate analysis, type 2 diabetes mellitus was an independent risk factor for severe steatosis (RR = 2.04, p = 0.023) and severe fibrosis (RR = 4.57, p = 0.013). Insulin therapy was significantly associated with non-alcoholic steatohepatitis (RR = 1.89, p = 0.001) and fibrosis (RR = 1.75, p = 0.050) when all patients were analysed, but when only patients with diabetes were analysed, insulin therapy was not associated with non-alcoholic steatohepatitis or fibrosis. Conclusion. Type 2 diabetes mellitus plays an important role in the progression of non-alcoholic fatty liver disease as an independent risk factor for severe fibrosis.     

Obesity-related non-alcoholic steatohepatitis and TGF-beta1 serum levels in relation to morbid obesity

Non-alcoholic steatohepatitis (NASH) can vary from mild hepatic inflammation and steatosis to cirrhosis, and is most frequently associated with obesity, Type 2 diabetes mellitus, hypertension, and the female gender. The prevalence of fatty liver and NASH in the general population is 20% and 3%, respectively. In Western countries, 15-20% of the population is obese and 74-90% of them exhibit fatty changes in liver biopsies. We assessed the prevalence of NASH in morbidly obese patients and evaluated serum TGF-beta1 concentrations in different stages of liver fibrosis. Thirty-five obese patients were evaluated, nine male and 26 female. Their mean body mass index (BMI) was 43.62 +/- 7.92 kg/m2. Liver biopsies were evaluated by light microscopy; graded and staged according to Brunt's system. Serum obtained from patients was used to detect TGF-beta1 concentrations by an ELISA method. Serum alanine transaminase (ALT) levels were elevated in four of the patients and the mean level was 49.98 +/- 94.7 (8-65 IU/L). NASH was diagnosed in 32 (91%) of the biopsies, and the most common pattern seen was mixed, predominantly macrovesicular steatosis. Some degree of fibrosis was seen in 34 (97%) of the biopsies and 22 (63%) were at stage 2 (range 1-3). Serum concentrations of TGF-beta1 had no relationship with the stages of fibrosis. In conclusion, NASH and fibrosis are common in our obese patients, as observed in other studies. TGF-beta1 may play a key role in liver fibrogenesis.