Transitional features of histologic type of non-alcoholic fatty liver disease in Korean young men

Background and Aim: The prevalence of non‐alcoholic fatty liver disease (NAFLD) is increasing in Korea as the dietary pattern and lifestyle become more Westernized and the obese population increases. The spectrum of NAFLD ranges from asymptomatic steatosis to non‐alcoholic steatohepatitis (NASH) and cirrhosis. Schwimmer et al. divided NASH into three types according to the histological characteristics, such as adult type, pediatric type and overlap type. We investigated clinical and histologic features of NAFLD patients in Korean young men. Methods: A total of 64 male patients under age 30 years, diagnosed as NAFLD by a liver biopsy, were reviewed retrospectively. NASH was diagnosed by NAFLD activity score (NAS), and NASH patients were classified with Schwimmer's histological classification. Results: Pathological features of liver biopsy revealed NASH in most cases (59 cases, 92.2%) including 29 cases (45.3%) of borderline NASH and 30 cases (46.9%) of definite NASH. The definite NASH group showed significantly high aspartate aminotransferase/alanine aminotransferase levels compared to the borderline NASH group. There were four cases (6.8%) of pediatric type, 17 cases (28.8%) of adult type, and 38 cases (64.4%) of overlap type in the NASH group. NAS was 3.75 ± 0.05 in the pediatric type, 4.29 ± 1.16 in the adult type and 4.87 ± 1.21 in the overlap type, and the overlap type showed a higher NAS than the pediatric type. The fibrosis stage was significantly higher in the overlap type than the other types. Conclusion: Most Korean young men with NAFLD turned out to have borderline or definite NASH. More than half of the NASH cases showed overlap type in Korean young men.     

Relationship between non-alcoholic fatty liver disease and pulmonary function

Background: It has been observed that non‐alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease and insulin resistance. Pulmonary function is also known to be related with cardiovascular disease and metabolic syndrome. Aims: The objective of this study was to investigate the association between NAFLD and pulmonary function. Methods: We performed a cross‐sectional study to examine the association of NAFLD based on abdominal sonographic findings and pulmonary function in 2119 Korean men between the ages of 30 and 75. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV₁) were compared according to the presence of NAFLD. Univariate and multivariate logistic regression analyses were conducted to evaluate the relationship of NAFLD with FVC and FEV₁ as pulmonary function tests. Results: The subjects with NAFLD had lower FVC and FEV₁ than their non‐steatotic counterparts, and FVC and FEV₁ gradually decreased according to the grade of hepatic steatosis. After adjusting for age, body mass index, smoking status, blood pressure, fasting plasma glucose, total cholesterol, hypertension, diabetes, triglyceride and high‐density lipoprotein cholesterol, the FVC and FEV₁ were found to be inversely associated with the presence of NAFLD. Conclusion: NAFLD was independently associated with reduced pulmonary function, and the severity of NAFLD was inversely correlated with pulmonary function.     

Recent concepts in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is present in up to one-third of the general population and in the majority of patients with metabolic risk factors such as obesity and diabetes. Insulin resistance is a key pathogenic factor resulting in hepatic fat accumulation. Recent evidence demonstrates NAFLD in turn exacerbates hepatic insulin resistance and often precedes glucose intolerance. Once hepatic steatosis is established, other factors, including oxidative stress, mitochondrial dysfunction, gut-derived lipopolysaccharide and adipocytokines, may promote hepatocellular damage, inflammation and progressive liver disease. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies, however, staging the disease requires a liver biopsy. NAFLD is associated with an increased risk of all-cause death, probably because of complications of insulin resistance such as vascular disease, as well as cirrhosis and hepatocellular carcinoma, which occur in a minority of patients. NAFLD is also now recognized to account for a substantial proportion of patients previously diagnosed with 'cryptogenic cirrhosis'. Diabetes, obesity and the necroinflammatory form of NAFLD known as non-alcoholic steatohepatitis, are risk factors for progressive liver disease. Current treatment relies on weight loss and exercise, although various insulin-sensitizing medications appear promising. Further research is needed to identify which patients will achieve the most benefit from therapy.     

Histopathological characteristics of non-alcoholic fatty liver disease in children: Comparison with adult cases

Aim: Non-alcoholic steatohepatitis (NASH) has been classified pathologically into type 1 (characterized by ballooning and perisinusoidal fibrosis) and type 2 (characterized by portal inflammation and portal fibrosis). Reportedly, type 2 NASH has been the most commonly observed histopathological feature in pediatric non-alcoholic fatty liver disease (NAFLD). While only a few studies have documented the histopathology of pediatric NAFLD so far, appropriate histopathological classification or characteristics of pediatric NAFLD, and the disease incidence correlation with race or ethnicity are still controversial. Methods: In this study, we compared the clinical and histopathological characteristics of NAFLD in 34 pediatric and 23 adult cases. Results: We found that pediatric steatosis was more severe than adult steatosis. Perisinusoidal fibrosis was significantly milder in pediatric cases than in adult cases. Lobular inflammation and ballooning was found to be milder in pediatric cases than in adult cases. On the other hand, portal inflammation was more severe in pediatric cases than in adult cases. The so-called borderline zone 1 NASH, similar to type 2 NASH, was observed in 21% of pediatric subjects; this rate was more than twice that in adult subjects. Fifty percent of pediatric cases showed overlapping features of types 1 and 2 NASH. Intralobular and portal changes showed positive and significant correlations with each other. Serum aminotransferase levels reflected the histopathological severity of NAFLD. Conclusion: We confirmed that pediatric NAFLD exhibits histopathological features that are different from adult NAFLD. The classification consisting of "type 1 NASH" and "type 2 NASH" may be impractical.     

Plasma reactive carbonyl species levels and risk of non-alcoholic fatty liver disease

Background and Aim: Oxidative stress plays a critical role in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD). However, there is still no large cohort study to explore the direct risk role of oxidative stress for NAFLD. This study is to test the hypothesis that elevated oxidative stress is a direct risk factor for the pathogenesis of NAFLD under controlling the potential effects of covariates. Methods: The levels of serum cholesterol, serum triglyceride, fasting plasma glucose and plasma reactive carbonyl species (RCS) were measured from 1204 Chinese Han adults, and the questionnaire and physical examination were administered to those with known and suspected risk factors for NAFLD. Results: Statistically significant high levels of blood pressure, fasting plasma glucose, serum cholesterol and triglyceride, body mass index, serum alanine aminotransferase and aspartate aminotransferase, and plasma RCS were observed in NAFLD subjects compared to healthy subjects (P < 0.01). Multivariate‐adjusted odds ratio illustrated that, compared with the lowest quartile of plasma RCS levels, the highest quartile subjects had a 132% increase in the risk of developing NAFLD. Further results from multi‐interaction analysis demonstrated that the underlying mechanism of the risk of NAFLD by unhealthy physical conditions and lifestyles might be, at least in part, through the oxidative stress. Conclusions: Our findings provide credible evidence from a large population that oxidative stress, as indicated by plasma RCS levels, may be a direct risk factor for developing NAFLD.     

Complex non-invasive fibrosis models are more accurate than simple models in non-alcoholic fatty liver disease

Background and Aim: Significant hepatic fibrosis is prognostic of liver morbidity and mortality in non‐alcoholic fatty liver disease (NAFLD); however, it remains unclear whether non‐invasive fibrosis models can determine this end‐point. We therefore compared the accuracy of simple bedside versus complex fibrosis models across a range of fibrosis in a multi‐centre NAFLD cohort. Methods: Simple (APRI, BARD) and complex (Hepascore, Fibrotest, FIB4) fibrosis models were calculated in 242 NAFLD subjects undergoing liver biopsy. Significant (F2‐4) and advanced fibrosis (F3,4) were defined using Kleiner criteria. Models were compared using area under the receiver operator characteristic curves (AUC). Cut‐offs were determined by Youden Index or 90% predictive values. Results: For significant fibrosis, non‐invasive fibrosis models had modest accuracy (AUC 0.707–0.743) with BARD being least accurate (AUC 0.609, P < 0.05 vs others). Using single cut‐offs, sensitivities and predictive values were < 80%; using two cut‐offs, > 75% of subjects fell within indeterminate ranges. Simple models had significantly more subjects within indeterminate ranges than complex models (99.1–100% vs 82.1–84.4% respectively, P < 0.05 for all). For advanced fibrosis, complex models were more accurate than BARD (AUC 0.802–0.858 vs 0.701, P < 0.05). Using two cut‐offs, complex models had fewer individuals within indeterminate ranges than BARD (11.1–32.3% vs 70.7%, P < 0.01 for all). For cirrhosis, complex models had higher AUC values than simple models. Conclusions: In NAFLD subjects, non‐invasive models have modest accuracy for determining significant fibrosis and have predictive values less than 90% in the majority of subjects. Complex models are more accurate than simple bedside models across a range of fibrosis.     

Difference in malignancies of chronic liver disease due to non-alcoholic fatty liver disease or hepatitis C in Japanese elderly patients

Aim: Malignancies that include hepatocellular carcinoma often occurred in patients with chronic liver disease. The aim of this retrospective match control study was to assess the cumulative development incidence and predictive factors for total malignancies in elderly Japanese patients with non‐alcoholic hepatic diseases (NAFLD) or hepatitis C virus (HCV). Methods: A total of 1600 NAFLD patients with age of ≥60 years were enrolled, and 1600 HCV patients with age of ≥60 years were selected as control by matching 1:1 with NAFLD group for age, sex, and follow‐up period. The primary goal is the first development of malignancies. Evaluation was performed by the use of the Wilcoxon rank sum test, the Kaplan–Meier method, and Cox proportional hazard model. The mean observation period is 8.2 years in both NAFLD and HCV group, respectively. Results: The number of patients with the development of malignancies was 167 in the NAFLD group and 395 in the HCV group. The 10th development rate of malignancies was 13.9% in the NAFLD group and 28.2% in the HCV group (risk ratio 2.27; P < 0.001). The incident rates of hepatocellular carcinoma in all the malignancies were 6.0% (10/167) in the NAFLD group and 67.6% (267/395) in the HCV group (P < 0.001). The malignancies in the NAFLD group were observed in the following order: gastric cancer 34 cases (20.4%) > colon cancer 31 cases (18.6%) > prostate cancer 21 cases (12.6%). Conclusions: The incident rates of hepatocellular carcinoma in all the malignancies were approximately 6% in the NAFLD group and two‐thirds in the HCV group.     

Nonalcoholic fatty liver disease – current status and future directions

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide with a reported prevalence ranging 6–33%, depending on the studied populations. It encompasses a spectrum of liver manifestations ranging from simple steatosis (also known as nonalcoholic fatty liver, NAFL) to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, which may ultimately progress to hepatocellular carcinoma. NAFLD is strongly associated with the components of metabolic syndrome, mainly obesity and type 2 diabetes mellitus. NAFLD patients are at increased risk of liver‐related as well as cardiovascular mortality. Current paradigm suggests a benign course for NAFL whereas NASH is considered to be the progressive phenotype. Although previously under‐recognized accumulating evidence suggests that NAFL may also progress, suggesting a higher number of patients at risk than previously appreciated. Liver biopsy remains the gold standard for definitive diagnosis, but the majority of patients can be diagnosed accurately by noninvasive methods. Approved therapies for NAFLD are still lacking and lifestyle modifications aiming at weight loss remain the mainstay of NAFLD treatment. Intensive research could identify insulin resistance, lipotoxicity and dysbiosis of the gut microbiota as major pathophysiological mechanisms, leading to the development of promising targeted therapies which are currently investigated in clinical trials. In this review we summarized the current knowledge of NAFLD epidemiology, natural history, diagnosis, pathogenesis and treatment and considered future directions.     

Increase in liver antioxidant enzyme activities in non-alcoholic fatty liver disease.

AIMS: Steatosis may increase oxidative stress, which is counteracted by cellular enzymatic (cytosolic and mitochondrial superoxide dismutases (Cu/Zn-SOD and Mn-SOD), glutathione peroxidase (GPx), catalase) and non-enzymatic antioxidant systems. We aimed to determine, in patients with non-alcoholic fatty liver disease (NAFLD), the level of antioxidant defenses (1) in liver biopsies, to demonstrate the existence of oxidative stress; (2) in erythrocytes and plasma, to determine whether their antioxidant defenses reflect liver oxidative stress. METHODS: Erythrocyte and plasma antioxidant defenses were prospectively studied in two groups of 16 patients: patients with NAFLD and controls. Liver biopsies were performed in eight NAFLD patients; liver antioxidant enzyme activities were measured and compared with those in 12 control livers used for transplantation. RESULTS: Cu/Zn-SOD, GPx and catalase activities were significantly higher in NAFLD livers than in controls whereas no significant differences were observed in Mn-SOD activity, and thiobarbituric acid-reactive substance (TBARS) concentration. No differences were observed in erythrocyte antioxidant enzyme activities (GPx, catalase, Cu/Zn-SOD), erythrocyte TBARS concentration, and plasma alpha-tocopherol concentration. CONCLUSIONS: Liver antioxidant enzyme activities were high in patients with NAFLD, reflecting an oxidative stress possibly involved in inflammation and fibrogenesis. However, erythrocyte and plasma antioxidant defenses did not reflect intrahepatic peroxidation.     

Usefulness of Technetium-99 m-2-methoxy-isobutyl-isonitrile liver scintigraphy for evaluating disease activity of non-alcoholic fatty liver disease

Aim: Non‐alcoholic steatohepatitis (NASH) is a progressive form of non‐alcoholic fatty liver disease (NAFLD). Therefore, it is important to evaluate disease activity and distinguish NASH from simple steatosis in NAFLD. Technetium‐99 m‐2‐methoxy‐isobutyl‐isonitrile (^99mTc‐MIBI) is a lipophilic cation designed for myocardial perfusion scintigraphy in the diagnosis of ischemic heart diseases, and its retention reflects mitochondrial function. It was reported that hepatic mitochondrial abnormalities would be an important predictive factor for NASH disease progression. The aim of this study was to examine the clinical usefulness of ^99mTc‐MIBI liver scintigraphy for evaluating disease activity of NAFLD and distinguishing NASH from simple steatosis in patients with NAFLD. Methods: Twenty‐six patients with biopsy‐proven NAFLD were enrolled. Clinicolaboratory tests and ^99mTc‐MIBI liver scintigraphy were performed. To evaluate hepatic uptake, regions of interest were set at the liver and heart, and the uptake ratio of the liver to heart (liver/heart ratio) was calculated. Results: All patients with NAFLD were classified into three groups according to the NAFLD activity score: non‐NASH (simple steatosis) (n = 4), borderline NASH (n = 11), and NASH (n = 11). Liver/heart ratios were significantly lower in NASH than in simple steatosis (P < 0.05). Moreover, liver/heart ratios were significantly correlated with NAFLD activity scores among the patients (r = ?0.413, P < 0.05). Conclusions: The present study indicates that ^99mTc‐MIBI liver scintigraphy would be a useful non‐invasive functional imaging method with which to evaluate disease activity of NAFLD and distinguish NASH from simple steatosis.     

Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world. It is closely associated with metabolic syndrome. The alarming epidemics of diabetes and obesity have fueled an increasing prevalence of NAFLD, particularly among these high-risk groups. Histologically, NAFLD encompasses a disease spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which is characterized by hepatocyte injury, inflammation, and variable degrees of fibrosis on liver biopsy. Non-alcoholic steatohepatitis can progress to cirrhosis in a fraction of patients. There is currently little understanding of risk factors for disease progression and the disease pathogenesis has not been fully defined. Liver biopsy remains the gold standard for diagnosis. Weight loss, dietary modification, and the treatment of underlying metabolic syndrome remain the mainstays of therapy once the diagnosis is established. There are no well-established pharmacological agents for treatment of NASH, although this is a subject of ongoing research.     

Increased prevalence of cardiovascular disease in Type 2 diabetic patients with non-alcoholic fatty liver disease.

AIMS: To estimate the prevalence of cardiovascular disease (CVD) in Type 2 diabetic patients with and without non-alcoholic fatty liver disease (NAFLD), and to assess whether NAFLD is independently related to prevalent CVD. METHODS: We studied 400 Type 2 diabetic patients with NAFLD and 400 diabetic patients without NAFLD who were matched for age and sex. Main outcome measures were prevalent CVD (as ascertained by medical history, physical examination, electrocardiogram and echo-Doppler scanning of carotid and lower limb arteries), NAFLD (by ultrasonography) and presence of the metabolic syndrome (MetS) as defined by the World Health Organization or Adult Treatment Panel III criteria. RESULTS: The prevalences of coronary (23.0 vs. 15.5%), cerebrovascular (17.2 vs. 10.2%) and peripheral (12.8 vs. 7.0%) vascular disease were significantly increased in those with NAFLD as compared with those without NAFLD (P < 0.001), with no differences between sexes. The MetS (by any criteria) and all its individual components were more frequent in NAFLD patients (P < 0.001). In logistic regression analysis, male sex, age, smoking history and MetS were independently related to prevalent CVD, whereas NAFLD was not. CONCLUSIONS: The prevalence of CVD is increased in patients with Type 2 diabetes and NAFLD in association with an increased prevalence of MetS as compared with diabetic patients without NAFLD. Follow-up studies are necessary to determine whether this higher prevalence of CVD among diabetic patients with NAFLD affects long-term mortality.     

Assessment of inflammation and fibrosis in non-alcoholic fatty liver disease by imaging-based techniques

Non-alcoholic fatty liver disease (NALFD) is a burgeoning global health problem, and the assessment of disease severity remains a clinical challenge. Conventional imaging and clinical blood tests are frequently unable to determine disease activity (the degree of inflammatory change) and fibrotic severity, while the applicability of histological examination of liver biopsy is limited. Imaging platforms provide liver-specific structural information, while newer applications of these technologies non-invasively exploit the physical and chemical characteristics of liver tissue in health and disease. In this review, conventional and newer imaging-based techniques for the assessment of inflammation and fibrosis in NAFLD are discussed in terms of diagnostic accuracy, radio-pathological correlations, and practical considerations. In particular, recent clinical studies of ultrasound (US)-based and magnetic resonance elastography techniques are evaluated, while the potential of contrast-enhanced US and magnetic resonance spectroscopy techniques is discussed. The development and application of these techniques is starting to reduce the clinical need for liver biopsy, to produce surrogate end-points for interventional and observational clinical studies, and through this, to provide new insights into the natural history of NAFLD.     

Colorectal neoplasms in relation to non-alcoholic fatty liver disease in Korean women: a retrospective cohort study

Background and Aim: Metabolic syndrome has been associated with an increased risk for colorectal cancer. Non‐alcoholic fatty liver disease (NAFLD) is regarded as a hepatic manifestation of metabolic syndrome. We investigated whether NAFLD is associated with colorectal neoplasms in Korean women. Methods: This retrospective cohort study included data from 5517 women, aged 35–80 years, who underwent life insurance company health examinations between July 2002 and June 2006. Fatty liver disease was assessed by abdominal ultrasound, with NAFLD defined as fatty liver disease in the absence of alcohol use of > 40 g/week or other secondary causes. The incidence of colorectal neoplasms through December 2008 was obtained through medical certificate codes for insurance claims. The association between NAFLD and the risk of colorectal neoplasms was estimated using standard Cox proportional hazards models. Results: Of the study population, 15.1% were diagnosed with NAFLD. During follow‐up, 65 women were verified as having adenomatous polyps and 15 as having colorectal cancer. Adjusted relative risks (95% confidence interval [CI]) for adenomatous polyps by age, low high‐density lipoprotein‐cholesterol, and NAFLD were 1.12 (95% CI 1.09–1.15), 2.56 (95% CI 1.53–4.28) and 1.94 (95% CI 1.11–3.40). Adjusted relative risks (95% CI) for colorectal cancer by age and NAFLD were 1.23 (95% CI 1.17–1.29) and 3.08 (95% CI 1.02–9.34). Conclusions: Our findings demonstrate a significant relationship between NAFLD and colorectal neoplasms. Among the various manifestations of metabolic syndrome, NAFLD may predict the development of colorectal neoplasms in Korean women.     

Genes or environment to determine alcoholic liver disease and non-alcoholic fatty liver disease.

While the vast majority of heavy drinkers and individuals with obesity, insulin resistance, and the metabolic syndrome will have steatosis, only a minority will ever develop steatohepatitis, fibrosis, and cirrhosis. Genetic and environmental risk factors for advanced alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of fibrosis. For ALD, the dose and pattern of alcohol intake, along with obesity are the most important environmental factors determining disease risk. For NAFLD, dietary saturated fat and antioxidant intake and small bowel bacterial overgrowth may play a role. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. For ALD, functional polymorphisms in the alcohol dehydrogenases and aldehyde dehydrogenase alcohol metabolising genes play a role in determining susceptibility in Oriental populations. No genetic associations with advanced NAFLD have been replicated in large studies. Preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, TNF-alpha, transforming growth factor-beta, and angiotensinogen may be associated with steatohepatitis and/or fibrosis.