Shivakumar Chitturi

Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.

affecting 20-30% of the general population, and recent studies indicate that fatty liver is an emerging problem in the Asia-Pacific region. 3 A comprehensive review of available data reveals that the overall prevalence of NAFLD in the Asia-Pacific region is broadly similar to that in North America, affecting between 12% and 24% of community subgroups. 4,5 The prevalence varies by age, gender, ethnicity, and locality (urban versus rural), as well as with criteria used for disease definition. 5 There is strong evidence that the prevalence of NAFLD in this region has increased substantially during the last 15 years in parallel with regional trends in over- nutrition (decreased physical activity with disproportionate food intake), central and overall obesity, type 2 diabetes mellitus (T2DM), and the metabolic syndrome. 6-8 Present trends in the obesity and diabetes pandemic indicate that a further increase in NAFLD prevalence is likely in the immediate future. 9,10

Non-alcoholic fatty liver disease in the Asia–Pacific region: Definitions and overview of proposed guidelines

Non‐alcoholic fatty liver disease (NAFLD) is the most common liver disorder in Western industrialized countries, affecting 20–40% of the general population. Large population‐based surveys in China, Japan, and Korea indicate that the prevalence of NAFLD is now 12% to 24% in population subgroups, depending on age, gender, ethnicity, and location (urban versus rural). There is strong evidence that the prevalence of NAFLD has increased recently in parallel with regional trends in obesity, type 2 diabetes, and metabolic syndrome; and that further increases are likely. The relationship between NAFLD, central obesity, diabetes, and metabolic syndrome is clearly evident in retrospective and prospective Asian studies, but the strength of association with these metabolic risk factors is only appreciated when regional definitions of anthropometry are used. Pathological definition of NAFLD, particularly its activity and the extent of liver fibrosis, requires histological examination, but liver biopsy is often not appropriate in this disorder for logistic reasons. An alternative set of operational definitions is proposed here. Clinicians need guidelines as how best to diagnose and manage NAFLD and its associated metabolic disorders in countries with scant healthcare resources. The Asia–Pacific Working Party (APWP) for NAFLD was convened to collate evidence and deliberate these issues. Draft proposals were presented and discussed at Asia–Pacific Digestive Week at Cebu, Philippines, in late November 2006, and are published separately in this issue of the Journal as an Executive Summary. The present document reviews the reasoning and evidence behind the APWP‐NAFLD proposals for definition, assessment, and management of NAFLD in the Asia–Pacific region.

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 10–15u2003years. 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 worlds 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.

Nonalcoholic fatty liver in Asia: Firmly entrenched and rapidly gaining ground.

Nonalcoholic fatty liver disease (NAFLD) is becoming an important chronic liver disorder in Asia. Prevalence figures show regional variations but at least 10% of the general population in Asia have fatty liver. Fatty liver can develop with relatively small changes in weight (2–3u2003kg), often with increasing central adiposity. The metabolic syndrome may precede or follow NAFLD. Overt diabetes is present in one‐third of cases but when oral glucose tolerance tests are performed, a further third of individuals have impaired glucose tolerance or diabetes. Natural history data are still scarce but cases of advanced hepatic fibrosis and hepatocellular carcinoma are now regularly reported. Many cases of cryptogenic cirrhosis are also attributable to NAFLD. Histological progression has been demonstrated for patients with NASH as well as for those with hepatic steatosis alone. Genetic factors may in part contribute to the rise in NAFLD. Polymorphisms within apolipoprotein C3 (APOC3) gene have been linked to NAFLD in lean Indian men. Although a number of other polymorphisms involving genes controlling adipose distribution, insulin signalling, adipokine responses and hepatic fibrosis have been reported, these studies have been underpowered. Transient elastography could help in detecting and monitoring hepatic fibrosis but further refinements in technique are necessary for obese individuals. Of the biomarkers, hyaluronic acid and cytokeratin‐18 fragment testing show promise as markers of hepatic fibrosis and NASH, respectively. Lifestyle alterations including dietary changes and increased physical activity remain the cornerstone of management. Attention should be paid to prevention through public education of campaigns addressing the increase in both adult and childhood obesity.

Hepatotoxic slimming aids and other herbal hepatotoxins.

Perceptions of safety and/or cultural mores prompt individuals to seek herbal slimming aids in preference to conventional dietary, physical activity and medication‐based protocols. In recent years, terpenoid‐containing dietary supplements have been implicated in causing severe and sometimes fatal hepatotoxicity. Teucrium polium (germander) was the first of these herbal products to be clearly linked to cases of acute liver failure. Subsequently, similar hepatotoxicity has been observed with other members of the Teucrium genus. While diterpenoid‐derived reactive metabolites are central to germander hepatotoxicity, it may also be that the hepatic effects of compounds such as Sho‐saiko‐to, Centella asiatica and Black cohosh are linked to their triterpenoid content. Other non‐terpenoid‐containing herbal remedies marketed for weight reduction have been causally associated with significant liver injury. Important among these are preparations containing N‐nitrosofenfluramine, usnic acid and ephedra alkaloids. Finally, we review recent data on known and emerging hepatotoxins such as Boh‐Gol‐Zhee, Kava, pyrrolizidine alkaloids and Shou‐Wu‐Pian. Better public and physician awareness through health education, early recognition and management of herbal toxicity and tighter regulation of complementary/alternative medicine systems are required to minimize the dangers of herbal product use.

TNF-α as therapeutic target in NASH: tried, but not yet proven

Nonalcoholic fatty liver disease (NAFLD) is now recognized as the commonest liver disorder in most industrialized countries, and affects 15–25% of many Asian populations. It is a metabolic liver disorder characterized by histological similarity to alcoholic liver disease in persons without excessive alcohol intake, and the pathological spectrum includes hepatic steatosis, nonalcoholic steatohepatitis (NASH) (steatosis plus hepatic inflammation, hepatocyte injury and fibrosis) and cirrhosis. Hepatic steatosis alone is a non-progressive condition, but up to one-third of individuals with NASH show progression in hepatic fibrosis. Individuals with NASH-related cirrhosis face a worrying outcome, with approximately one in 10 dying from liver failure over 7 years. In population-based studies of all types of NAFLD, rates of liverrelated mortality are much lower (~2%), but liver disease may rank as highly as the third most common cause of death. The pathogenesis of NAFLD has been conceptualized as hepatic fat accumulation as the first step, followed by superimposed secondary insult(s), the “two hit” hypothesis. Among the latter, diverse processes ranging from oxidative stress, impaired mitochondrial function through to genetically determined differences in inflammatory recruitment and metabolic disposal pathways have been implicated. However, with the understanding that many of these processes (e.g. oxidative stress) could qualify equally as a “primary” or a “secondary” hit, NAFLD/NASH is now viewed as the culmination of multiple interactive rather than sequential pathways. Current treatment strategies against NAFLD and NASH are directed at individual pathways considered critical in promoting liver injury. Apart from attempts to reverse steatosis by lifestyle and weight-reducing measures, these include attempts at reducing oxidative stress (vitamin E, glutathione precursors such as betaine, N-acetylcysteine), improving insulin sensitivity (metformin, thiazolidinediones [TZD]) or by promoting intrahepatic fatty acid b-oxidation by using peroxisomal proliferator-activated receptor (PPAR-a) agonists (bezafibrate). Others have directed their efforts towards reducing bacterial endotoxemia (antimicrobials), blocking triglyceride absorption (Orlistat, a gastric lipase inhibitor), inhibiting renin-angiotensin activation (Losartan) or by simply focusing on management of the other components of the associated metabolic syndrome (hyperlipidemia and type 2 diabetes). Unfortunately, the studies of NASH treatment to date have been plagued with methodological problems: small sample sizes, nonrandomized or uncontrolled observations, absence of posttreatment histology and short follow up. A particularly crucial issue is the interpretation of uncontrolled “positive” studies because of the impressive responses in placebo recipients and also the lack of correlation between changes in serum enzyme levels and liver histology. To date, level I evidence is available only for bariatric surgery (which is effective) and for ursodeoxycholic acid, which is not different from placebo. Of the drugs available, insulin-sensitizing agents (TZD, metformin) are regarded as leading contenders in the field. However, the overall experience with metformin is yet to justify its routine use. In a systematic review of nine studies with metformin, most involved small sample sizes (median, n = 18). Although insulin resistance indices improved, serum transaminases decreased in only a third and reduced hepatic inflammatory activity was noted in only one trial. In another recent study reported in abstract form, only those patients taking metformin who lost weight had improvement in steatosis. Trials with TZD have shown more impressive reduction in hepatic steatosis, necroinflammatory activity and fibrosis. However, weight gain (up to 4% of baseline body weight), lack of sustained response after drug withdrawal, adverse effects and high cost are problems that need addressing. The fact that none of the drugs tested so far satisfy strict levels of evidence to validate their use mandates a search for alternative approaches to treatment. One such strategy may be targeting tumor necrosis factor (TNF)-a. Cytokine mobilization, particularly TNF-a, is one of many processes implicated in hepatic inflammatory cell recruitment in NASH, the key step in initiation and perpetuation of liver injury. Further, by impairing insulin receptor signaling, TNF-a can also reduce insulin sensitivity, thereby causing or worsening insulin resistance, a key part of the pathophysiology of NAFLD/NASH. Some investigators have invoked a pivotal role for this cytokine in NASH because serum TNF-a is increased in human and experimental NAFLD, although at least one study found no difference between steatosis and NASH. Further, there are now reports of experimental steatohepatitis occurring in mice with metabolic syndrome in the absence of TNF-a receptor signaling. These observations cast doubt on the essential relevance of TNF-a as a primary mediator of inflammatory cell recruitment in NASH. However TNF-a, like many other cytokines, has multiple effects and its influence on other pathophysiological processes such as insulin signaling cannot be discounted. Pentoxifylline, a phosphodiesterase inhibitor, is an agent that has been shown to attenuate the production of TNF-a and other Accepted for publication 8 February 2007.

Clues from the carotids: An appraisal of cardiovascular disease risk in non-alcoholic fatty liver disease

In this issue of the Journal of Gastroenterology and Hepatology, Wang et al. report that patients with non-alcoholic fatty liver disease (NAFLD) and raised serum alanine aminotransferase (ALT) have an increased risk of carotid atherosclerosis. Their study involved 170 subjects recruited from the Buddhist Tzu Chi General hospital in Taiwan. The diagnosis of NAFLD was made by liver ultrasound and exclusion of other causes of hepatic steatosis. The NAFLD group was further subdivided based on the levels of ALT into those with normal (n = 72) and those with raised ALT levels (n = 29). All their subjects were screened for the presence of metabolic disorders (obesity, hypertension, dyslipidemia, type 2 diabetes). In addition, they underwent ultrasound evaluation of both common carotid arteries for evidence of carotid atherosclerosis. Measurements of carotid intima-media thickness (IMT) were obtained and screening for carotid plaques was carried out; participants with carotid IMT readings of greater than 1 mm were designated as having carotid atherosclerosis. Persons with normal liver ultrasound findings served as controls (n = 69). As expected, their subjects with NAFLD were more likely to fulfil criteria for metabolic syndrome (MetS) than controls (55% with raised ALT, 22% with normal ALT and 4% of controls). The authors go on to show that subjects with NAFLD, particularly those with raised ALT, have a significantly higher prevalence of carotid atherosclerosis than controls (41% vs 18%, respectively). Further, within the NAFLD group, an incremental increase in ALT was an independent predictor of carotid atherosclerosis; for every 10 IU increase in ALT, the odds ratio for developing these carotid changes was 1.44. The authors conclude that raised ALT can serve as a surrogate marker for cardiovascular disease (CVD) in persons with fatty liver. Are these findings novel and, if confirmed, what are the implications? Before addressing these questions, it is necessary to review our current understanding of the place of NAFLD among metabolic disorders and its association with CVD. Although association with MetS has been alluded to earlier, definitive studies establishing NAFLD as the hepatic manifestation of MetS have been more recent. In addition, patients with NAFLD are at risk of developing other metabolic disorders with follow up. For instance, there is a threeto fourfold likelihood of developing type 2 diabetes and hypertension within a decade of diagnosis. While these studies have firmly placed NAFLD amidst the constellation of disorders that constitute MetS, the real test of inclusion is whether NAFLD is also associated with a greater risk of CVD and type 2 diabetes. After all, it has been known for many years that persons with MetS have a twoto threefold risk of developing CVD and a fivefold risk of type 2 diabetes. Of these two disorders, the association with type 2 diabetes (more specifically, insulin resistance) is well recognized; type 2 diabetes or impaired glucose tolerance is present in 30% to 40% of patients with fatty liver. With respect to CVD risk, the most compelling data come from natural history studies of NAFLD. While these studies have been instructive in highlighting the potential for liver-related complications among certain subgroups, they also uniformly document CVD as one of the leading causes of death. In recent years, the NAFLD-cardiovascular link has undergone further scrutiny. Because it is difficult to conduct large, prospective and longitudinal studies on cardiovascular outcomes, several research groups have focused instead on surrogate markers for CVD. These include studies of intramyocardial resistance, endothelial flow-mediated vasodilation, basilar artery pulsatility index and carotid IMT measurement. Of these, the latter isperhaps the most widely studied surrogate marker for CVD in fatty liver cohorts. In addition to measuring IMT, carotid plaques are also visualized. Carotid IMT is not synonymous with carotid atherosclerosis and should be regarded as a biomarker of ‘vascular age’. However, it is often used interchangeably (as in this study by Wang et al.) to connote cardiac atherosclerosis. Its value as a biomarker of CVD is supported by a recent meta-analysis; for every 0.1 mm common carotid IMT difference, the CVD risk was increased by 1.15. In terms of absolute risk, carotid IMT readings greater than 1.06 mm were associated with a 2% risk of myocardial infarction and stroke. Like many biological variables (serum cholesterol, blood glucose, blood pressure), there is likely to be a continuum of risk rather than an abrupt ‘cut-off’. How do we interpret the carotid IMT findings in the current study? In keeping with other recent publications (Table 1), there were significant differences in carotid IMT between patients with NAFLD and controls. The authors have wisely chosen a relatively high cut-off of 1 mm to represent significant carotid disease. Many, but not all, studies listed in the table have identified NAFLD as an independent predictor of increased carotid IMT and, by inference, CVD risk. To reiterate this important point, this finding implies that the CVD risk for patients with NAFLD is greater than that which could be attributed to the individual MetS components alone. Unfortunately, a limitation of the study by Wang et al. is that the cohort was probably too small to conduct a multivariate analysis of the entire cohort to answer this question. However, as mentioned above, they confined their analysis to the NAFLD group; age, male gender and ALT emerged as significant predictors of carotid IMT. The relevance of age and gender to the process of atherosclerosis is well documented and need not be considered any further. However, incremental ALT changes and the risk of CVD bear comment. Subanalyses of large population studies have shown that elevated liver enzymes (gamma-glutamyl transpeptidase and also Accepted for publication 29 May 2009.

Adipocytokine polymorphisms and nonalcoholic fatty liver disease

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Octreotide as a bridge to definitive surgery in a patient with cirrhosis and a large spontaneous abdominal wall haematoma: Letters to the Editor

a snowboarder, resulting in aortic dissection in a bovine aortic arch. Interestingly, our patient also had a bovine arch although there are varying reports on whether bovine arches, which are anchored by only two great vessels, are more predisposed to dissection. Lower impact interscapular back blows administered as first aid have been implicated in causing fatal aortic dissection from rupture of a penetrating atherosclerotic ulcer. Their case study shared many similarities with ours, and indeed our patient had a risk factor profile that was more predisposed to rupture of a penetrating atherosclerotic ulcer. Aortic dissection, regardless of the cause, carries a high mortality and we accept that this patient died of natural causes. We aim to raise the possibility of an association, without implying definite causality, between the current recommended interventions for choking and thoracic aortic dissection in older patients with heightened vascular risks.