What are the risk factors and settings for non‐alcoholic fatty liver disease in Asia–Pacific?

The risk factors and settings for non-alcoholic fatty liver disease (NAFLD) in Asians are reviewed comprehensively. Based particularly on large community-based studies using ultrasonography, case-control series and prospective longitudinal studies, the prevalence of NAFLD in Asia is between 12% and 24%, depending on age, gender, locality and ethnicity. Further, the prevalence in China and Japan has nearly doubled in the last 10-15 years. A detailed analysis of these data shows that NAFLD risk factors for Asians resemble those in the West for age at presentation, prevalence of type 2 diabetes mellitus (T2DM) and hyperlipidemia. The apparent differences in prevalence of central obesity and overall obesity are related to criteria used to define waist circumference and body mass index (BMI), respectively. The strongest associations are with components of the metabolic syndrome, particularly the combined presence of central obesity and obesity. Non-alcoholic fatty liver disease appears to be associated with long-standing insulin resistance and likely represents the hepatic manifestation of metabolic syndrome. Not surprisingly therefore, Asians with NAFLD are at high risk of developing diabetes and cardiovascular disease. Conversely, metabolic syndrome may precede the diagnosis of NAFLD. The increasing prevalence of obesity, coupled with T2DM, dyslipidemia, hypertension and ultimately metabolic syndrome puts more than half the world's population at risk of developing NAFLD/non-alcoholic steatohepatitis/cirrhosis in the coming decades. Public health initiatives are clearly imperative to halt or reverse the global 'diabesity' pandemic, the underlying basis of NAFLD and metabolic syndrome. In addition, a perspective of NAFLD beyond its hepatic consequences is now warranted; this needs to be considered in relation to management guidelines for affected individuals.     

Addressing different biases in analysing drug use on cancer risk in diabetes in non‐clinical trial settings—what,why and how?

Motivated by recent reports on associations between diabetes and cancer, many researchers have used administrative databases to examine risk association of cancer with drug use in patients with diabetes. Many of these studies suffered from major biases in study design and data analysis, which can lead to erroneous conclusions if these biases are not adjusted. This article discusses the sources and impacts of these biases and methods for correction of these biases. To avoid erroneous results, this article suggests performing sensitivity and specificity analysis as well as using a drug with a known effect on an outcome to ascertain the validity of the proposed methods. Using the Hong Kong Diabetes Registry, we illustrated the impacts of biases of drug use indication and prevalent user by examining the effects of statins on cardiovascular disease. We further showed that 'immortal time bias' may have a neutral impact on the estimated drug effect if the hazard is assumed to be constant over time. On the contrary, adjustment for 'immortal time bias' using time-dependent models may lead to misleading results biased towards against the treatment. However, artificial inclusion of immortal time in non-drug users to correct for immortal time bias may bias the result in favour of the therapy. In conclusion, drug use indication bias and prevalent user bias but not immortal time bias are major biases in the design and analysis of drug use effects among patients with diabetes in non-clinical trial settings.     

Arterial hypertension and glycemia in non‐diabetic subjects: is there an association independent of obesity?

Background

A possible association of glycemia with arterial hypertension has been suggested by the frequent co‐occurrence of impaired glucose tolerance or Type 2 diabetes mellitus with arterial hypertension. The objective was to examine the relationship of glycated hemoglobin (HbA_1c) concentration with arterial hypertension status in non‐diabetic subjects.

Methods

A cross‐sectional analysis of baseline data from the EPIC‐Potsdam Cohort Study, Germany, was performed. The study population comprised 1846 non‐diabetic subjects, 772 men and 1074 women, age 35–65. Blood pressure was measured three times consecutively. Level of HbA_1c was determined by an assay based on monoclonal antibodies. Body height, weight and circumferences were obtained. Arterial hypertension status was either determined through blood pressure measurement (blood pressure ≥160/95 mmHg) or based on antihypertensive drug use. HbA_1c was divided into sex‐specific quintiles and logistic regression was used to estimate the odds of being hypertensive and the corresponding confidence intervals.

Results

The highest compared to the lowest quintiles of HbA_1c were in univariate analysis associated with being hypertensive. Adjustment for age and body mass index completely removed any significant association with arterial hypertension status. The odds ratio in men was 1.1 (95% CI 0.7–1.8), and in women it was 0.9 (95% CI 0.5–1.4). Repeating the analysis with systolic and diastolic blood pressure among untreated hypertensives yielded similar results.

Conclusion

Unlike previous studies, our data do not support an association of HbA_1c with arterial hypertension that is statistically independent of age and body mass index. Whether these established arterial hypertension risk factors are truly confounders of the HbA_1c‐arterial hypertension association or rather potentially antecedent factors requires further study. Copyright © 1999 John Wiley & Sons, Ltd.

     

Coffee and non‐alcoholic fatty liver disease: Brewing evidence for hepatoprotection?

Coffee is one of the most popular beverages in the world. Several studies consistently show that coffee drinkers with chronic liver disease have a reduced risk of cirrhosis and a lower incidence of hepatocellular carcinoma regardless of primary etiology. With the increasing prevalence of non‐alcoholic fatty liver disease (NAFLD) worldwide, there is renewed interest in the effect of coffee intake on NAFLD severity and positive clinical outcomes. This review gives an overview of growing epidemiological and clinical evidence which indicate that coffee consumption reduces severity of NAFLD. These studies vary in methodology, and potential confounding factors have not always been completely excluded. However, it does appear that coffee, and particular components other than caffeine, reduce NAFLD prevalence and inflammation of non‐alcoholic steatohepatitis. Several possible mechanisms underlying coffee's hepatoprotective effects in NAFLD include antioxidative, anti‐inflammatory, and antifibrotic effects, while a chemopreventive effect against hepatocarcinogenesis seems likely. The so‐far limited data supporting such effects will be discussed, and the need for further study is highlighted.     

Hepatocellular carcinoma in non‐alcoholic steatohepatitis: Growing evidence of an epidemic?

The incidence of hepatocellular carcinoma in non‐viral‐related chronic liver disease has gradually increased in Japan. Obesity and diabetes mellitus type 2 have been established as a significant risk factor for hepatocellular carcinoma (HCC) by epidemiologic observations and experimental studies. The risks of these factors for HCC are likely conferred by two factors: the increased risk for development of non‐alcoholic steatohepatitis (NASH) and the carcinogenic potential of themselves. Hepatocellular carcinoma in NASH is difficult to evaluate because histological diagnosis is required for diagnosis of NASH, which can lead selection bias. Furthermore, end‐stage NASH is in effect “burned‐out” NASH, for which the diagnosis of NASH cannot be made any more. At all events, previous studies on the etiology of Japanese HCC showed that non‐alcoholic fatty liver disease accounts for 1–5% of all HCC (male predominant, median age 72 years). They have high prevalences of obesity and/or diabetes mellitus type 2 and 10–75% of the HCC arose from non‐cirrhotic livers. HCC in NASH may be of multicentric origin, similar to HCC based on viral hepatitis. Regular screening for HCC is extremely important especially in cirrhotic NASH patients and recurrence should be warned. In western and Asian countries, the prevalence of non‐alcoholic fatty liver disease in the general population is increasing dramatically. Therefore, there is an urgent need to elucidate pathogenesis and clinical features of HCC in NASH. In this review we summarize current concepts for HCC in NASH.     

How common is non‐alcoholic fatty liver disease in the Asia–Pacific region and are there local differences?

Risk factors for development of non-alcoholic steatohepatitis include obesity, especially central adiposity, glucose intolerance or type 2 diabetes mellitus (T2DM), and dyslipidemia. Non-alcoholic fatty liver disease (NAFLD) is now considered a manifestation of metabolic syndrome. During the last two decades, NAFLD has become the most common chronic liver disease in North America and Europe, but until recently was thought to be uncommon (perhaps due to the lack of study) in Asia. Fatty liver can be identified on imaging modalities (ultrasonography, computed tomography scans, and magnetic resonance imaging) with high sensitivity, but steatohepatitis and fibrosis cannot be distinguished. Thus, an inherent drawback in studying the epidemiology of NAFLD is the lack of definitive laboratory tests, no uniform definition-with different studies using cut-off values of alcohol consumption from <20 g/week to 210 g/week, and case selections where biopsy was used for definition. In studies outside the region, the prevalence of NAFLD varies from 16% to 42% by imaging, and 15-39% of liver biopsies. The major risk factors for NAFLD, central obesity, T2DM, dyslipidemia, and metabolic syndrome, are now widely prevalent and are increasing geometrically in the Asia-Pacific region. It is therefore not surprising that NAFLD is common in this region. Estimates of current prevalence range from 5% to 30%, depending on the population studied. Central obesity, diabetes, and metabolic syndrome are the major risk factors. To date, however, data on the natural history and impact of NAFLD causing serious significant chronic liver disease are lacking and there is a need for prospective, cooperative studies.     

Ultrio and Ultrio Plus non‐discriminating reactives: false reactives or not?

Background The low, fluctuating levels of DNA characteristic of occult hepatitis B infection make its detection by nucleic acid testing (NAT) a challenge. Methods Four year’s routine use of the Ultrio and Ultrio Plus assays in blood donations in New Zealand was analysed. Results 0·09% of donations tested with Ultrio and Ultrio Plus assays showed reactivity in the multiplex assay, but non‐reactivity in all three discriminatory assays and relevant mandatory serological assays (anti‐HIV, anti‐HCV, HBsAg). These donations were more likely to be anti‐HBc reactive (Ultrio, 13%; Ultrio Plus, 57%; random donors, 6·8%). Thirty‐four per cent of these anti‐HBc‐reactive donations were also reactive in either an alternate NAT assay or on repeat multiplex testing. Thirteen per cent of the donors of the discriminatory‐negative, anti‐HBc‐reactive donations who had given other Ultrio‐ or Ultrio Plus‐tested donations had at least one other multiplex reactive donation. Conclusion These findings suggest that their HBV DNA levels are around the assay’s limit of detection, that false reactivity cannot be presumed when a donor fails to discriminate and that caution should be applied when deciding whether to continue accepting donations from such donors.     

Are mosquitoes diverted from repellent‐using individuals to non‐users? Results of a field study in Bolivia

Outside sub-Saharan Africa, Anopheline mosquito exophagic and/or crepuscular behaviour patterns imply that insecticide-treated nets may provide incomplete protection from malaria-infective mosquito bites. Supplementary repellent treatment has been recommended in such circumstances, especially where vectors are exophilic and so are not susceptible to residual insecticide spraying. As maintaining complete usage of repellents in a community is unrealistic, the potential negative impact on non-users of repellent usage by 'neighbours' in the same community needs to be addressed in the context of health policy promoting equity. This study quantifies diversion of host-seeking mosquitoes, from repellent wearing to unprotected individuals, 1 m apart under field conditions in Bolivia. Each of the six volunteer-pairs sat >20 m apart from other pairs. Volunteers were allocated di-ethyl toluamide (DEET) or mineral oil in ethanol control. Treatments were rotated, so that during the trial, both pair-members wore repellent on 72 occasions; both pair-members wore control on 72 occasions; and on 36 occasions, one pair-member wore repellent and the other control. Unprotected (control) pair-members received 36.4% [95% confidence interval (CI): 8.1-72.0%] more Anopheles darlingi landings (P = 0.0096) and 20.4% (95% CI: 0.6-44.0%) more mosquito landings (P = 0.044), when their 'partner' wore repellent than when their partner also wore control. A second, smaller Latin-square trial using 30% lemongrass (Cymbopogon citratus) repellent, with control, obtained 26.0% (95% CI: 5.2-51.0%) more mosquito landings when controls sat with repellent-wearers rather than other controls (P = 0.0159). With incomplete community repellent usage, non-users could be put at an increased risk of malaria. The results also have implications for repellent-efficacy assay design, as protection will appear magnified when mosquitoes are given a choice between repellent-users and non-users.     

Electron microscopic findings in non‐alcoholic fatty liver disease: Is there a difference between hepatosteatosis and steatohepatitis?

Background and Aims: Non‐alcoholic fatty liver disease has long been accepted as benign; however, recent evidence suggests that the disease may progress to cirrhosis and hepatocellular carcinoma, although the natural course of the disease is still unclear. This study was designed to comparatively evaluate electron microscopic features of non‐alcoholic fatty liver (NAFL) and non‐alcoholic steatohepatitis (NASH). Methods: Quantitative and semi‐quantitative ultrastructural evaluations were performed on liver biopsies from 23 patients, 10 with NAFL and 13 with NASH. Results: No statistically significant difference was noted between NAFL and NASH patients in ultrastructural features of hepatocytes including megamitochondria, intramitochondrial crystalline inclusions, mitochondrial matrix granules, foamy cytoplasmic appearance, electron‐lucent and glycogen‐containing nuclear regions, lipofuscin granules, or an increased frequency of vesicles containing electron‐dense material in peribiliary Golgi zone; however, the mitochondrial diameter was significantly higher in the NASH patients. Intercellular distance and microvilli between hepatocytes, collagen and electron‐dense material accumulation in the space of Disse, electron‐dense material accumulation and microvillus density in bile canaliculi did not differ significantly between the groups. Conclusions: Our data show that, although NAFL and NASH can be distinguished by their distinct light microscopic features, ultrastructural characteristics are similar, which suggests that NAFL may also have the potential to progress to fibrosis and cirrhosis like NASH.