Jason M. Hui

The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD.

Patients with nonalcoholic fatty liver disease (NAFLD) and advanced liver fibrosis are at the highest risk for progressing to end‐stage liver disease. We constructed and validated a scoring system consisting of routinely measured and readily available clinical and laboratory data to separate NAFLD patients with and without advanced fibrosis. A total of 733 patients with NAFLD confirmed by liver biopsy were divided into 2 groups to construct (n = 480) and validate (n = 253) a scoring system. Routine demographic, clinical, and laboratory variables were analyzed by multivariate modeling to predict presence or absence of advanced fibrosis. Age, hyperglycemia, body mass index, platelet count, albumin, and AST/ALT ratio were independent indicators of advanced liver fibrosis. A scoring system with these 6 variables had an area under the receiver operating characteristic curve of 0.88 and 0.82 in the estimation and validation groups, respectively. By applying the low cutoff score (−1.455), advanced fibrosis could be excluded with high accuracy (negative predictive value of 93% and 88% in the estimation and validation groups, respectively). By applying the high cutoff score (0.676), the presence of advanced fibrosis could be diagnosed with high accuracy (positive predictive value of 90% and 82% in the estimation and validation groups, respectively). By applying this model, a liver biopsy would have been avoided in 549 (75%) of the 733 patients, with correct prediction in 496 (90%). Conclusion: a simple scoring system accurately separates patients with NAFLD with and without advanced fibrosis, rendering liver biopsy for identification of advanced fibrosis unnecessary in a substantial proportion of patients. (HEPATOLOGY 2007;45:846–854.)

Beyond insulin resistance in NASH: TNF-α or adiponectin?

Adiponectin has antilipogenic and anti‐inflammatory effects, while tumor necrosis factor α (TNF‐α) reduces insulin sensitivity and has proinflammatory effects. We examined (1) the extent to which hypoadiponectinemia and TNF‐α activation are features of nonalcoholic steatohepatitis (NASH) and (2) whether serum levels of these markers correlate with the severity of histological changes in 109 subjects with nonalcoholic fatty liver disease (NAFLD), including 80 with NASH and 29 with simple steatosis. By multivariate analysis, subjects with NASH had reduced adiponectin level and increased TNF‐α and soluble TNF receptor 2 (sTNFR2)—but not leptin levels, compared with controls matched by age, sex, and body mass index; these differences were independent of the increased insulin resistance (by homeostasis model [HOMA‐IR]) in NASH. When compared with simple steatosis, NASH was associated with lower adiponectin levels and higher HOMA‐IR, but there were no significant differences in the levels of TNF‐α and sTNFR2. The majority of subjects with steatohepatitis (77%) had adiponectin levels less than 10 μg/mL and HOMA‐IR greater than 3 units, but only 33% of those with pure steatosis had these findings. HOMA‐IR and low serum adiponectin were also independently associated with increased grades of hepatic necroinflammation. In conclusion, hypoadiponectinemia is a feature of NASH independent of insulin resistance. Reduced adiponectin level is associated with more extensive necroinflammation and may contribute to the development of necroinflammatory forms of NAFLD. (HEPATOLOGY 2004;40:46–54.)

Visceral fat: A key mediator of steatohepatitis in metabolic liver disease†

Visceral obesity is intimately associated with metabolic disease and adverse health outcomes. However, a direct association between increasing amounts of visceral fat and end‐organ inflammation and scarring has not been demonstrated. We examined the association between visceral fat and liver inflammation in patients with nonalcoholic fatty liver disease (NAFLD) to delineate the importance of visceral fat to progressive steatohepatitis and hence the inflammatory pathogenesis of the metabolic syndrome. We undertook a cross‐sectional, proof of concept study in 38 consecutive adults with NAFLD at a tertiary liver clinic. All subjects had a complete physical examination, anthropometric assessment, and fasting blood tests on the day of liver biopsy. Abdominal fat volumes were assessed by magnetic resonance imaging within 2 weeks of liver biopsy. The extent of hepatic inflammation and fibrosis augmented incrementally with increases in visceral fat (P < 0.01). For each 1% increase in visceral fat, the odds ratio for increasing liver inflammation and fibrosis was 2.4 (confidence interval [CI]: 1.3‐4.2) and 3.5 (CI: 1.7‐7.1), respectively. Visceral fat remained an independent predictor of advanced steatohepatitis (odds ratio [OR] 2.1, CI: 1.1‐4.2, P = 0.05) and fibrosis (OR 2.9, CI: 1.4‐6.3, P = 0.006) even when controlled for insulin resistance and hepatic steatosis. Interleukin‐6 (IL‐6) levels, which correlated with visceral fat, also independently predicted increasing liver inflammation. Visceral fat was associated with all components of the metabolic syndrome. Conclusion: Visceral fat is directly associated with liver inflammation and fibrosis independent of insulin resistance and hepatic steatosis. Visceral fat should therefore be a central target for future interventions in nonalcoholic steatohepatitis and indeed all metabolic disease. (HEPATOLOGY 2008.)

The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: An international collaborative study†‡§

Information on the long‐term prognosis of nonalcoholic fatty liver disease (NAFLD) is limited. We sought to describe the long‐term morbidity and mortality of patients with NAFLD with advanced fibrosis or cirrhosis by prospectively studying 247 such patients from four international centers (in Australia, USA, UK and Italy). Their natural history was then compared with 264 patients with HCV infection who were either naïve or non‐responders to treatment. Both cohorts were Child‐Pugh class A and had advanced fibrosis (stage 3) or cirrhosis (stage 4) confirmed by liver biopsy at enrollment. In the NAFLD cohort, followed up for a mean of 85.6 months (range, 6‐297), there were 48 (19.4%) liver‐related complications and 33 (13.4%) deaths or liver transplants. In the HCV cohort, followed up for 74.9 months (mean; range, 6‐238), there were 47 (16.7%) liver‐related complications and 25 (9.4%) deaths or liver transplants. When adjusting for baseline differences in age and gender, the cumulative incidence of liver‐related complications was lower in the NAFLD than the HCV cohort (P = 0.03), including incident hepatocellular cancer (6 versus 18; P = 0.03), but that of cardiovascular events (P = 0.17) and overall mortality (P = 0.6) were similar in both groups. In the NAFLD cohort, platelet count, stage 4 fibrosis, lowered platelet count, and lowered serum cholesterol and alanine aminotrasferase (ALT) levels were associated with liver‐related complications; an aspartate aminotransferase/ALT ratio >1 and older age were associated with overall mortality, and higher serum bilirubin levels and stage 4 fibrosis were associated with liver‐related mortality. Conclusions: Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver‐related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality. Some clinical and laboratory features predict liver‐related complications and other outcomes in patients with NAFLD. (HEPATOLOGY 2011;54:1208–1216)

Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index.

We sought to develop a clinically useful index comprising standard and physiologically relevant variables to predict the probability of significant hepatic fibrosis in subjects with chronic hepatitis C virus (HCV) infection. Fibrosis was graded as mild (stages F0 or F1) or significant (stages F2–F4). Thirty‐five clinical and laboratory parameters were analyzed initially in 176 patients with detectable HCV RNA to derive a fibrosis probability index (FPI) to predict significant fibrosis. This index then was validated in a second group of 126 subjects. Among 18 variables associated with severe fibrosis on univariate analysis, multiple logistic regression analysis identified age, aspartate aminotransferase (AST), total cholesterol level, insulin resistance (by homeostasis model), and past alcohol intake as independent predictors of significant fibrosis. The area under the receiver operating characteristic (ROC) curves was 0.84 for the initial cohort and 0.77 for the validation cohort. In the initial cohort, the sensitivity of the FPI based on these five predictors was 96%, and the negative predictive value was 93% at a score of ≥0.2. At scores ≥0.8, the FPI was 94% specific and had a positive predictive value of 87%. In conclusion, an FPI using routinely assessed markers and incorporating a measure of insulin resistance can reliably predict the probability of significant hepatic fibrosis in most patients with chronic HCV infection. Such an index should prove useful to guide decision making regarding the need for liver biopsy, and potentially for avoiding or deferring biopsy in a large proportion of patients with mild liver disease. (HEPATOLOGY 2004;39:1239–1247.)

Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection

Abstract Background: Hepatic steatosis is common in hepatitis C, but the relative importance of host and viral factors is controversial. In the present prospective study, we examined metabolic factors associated with non‐alcoholic fatty liver and viral genotype as predictors of steatosis and fibrosis in chronic hepatitis C infection.

Insulin resistance and liver injury in hepatitis C is not associated with virus‐specific changes in adipocytokines

The role of tumor necrosis factor α, interleukin 6, leptin, and adiponectin in the pathogenesis of hepatitis C virus (HCV)‐associated insulin resistance (IR) remains controversial. We tested the hypothesis that these adipocytokines contribute to chronic HCV‐associated IR and liver injury by first comparing their serum levels and homeostasis model assessment of insulin resistance (HOMA‐IR) in 154 untreated, non‐diabetic, HCV‐infected male subjects with fibrosis stage 0‐2, to that in 75 healthy volunteers matched for age, body mass index (BMI), and waist‐hip ratio (WHR). We next examined whether the adipocytokine levels were associated with the extent of hepatic steatosis, portal/periportal inflammation and fibrosis in our total cohort of 240 HCV‐infected male subjects. Significantly higher levels of HOMA‐IR (2.12 versus 1.63, P = 0.01), TNFα (1.28 versus 0.60 pg/ml, P < 0.001) and IL6 (2.42 versus 1.15 pg/ml, P = 0.001) were noted in the HCV cohort compared with healthy controls respectively, but there were no significant differences in leptin and adiponectin concentrations. By multiple linear regression, independent predictors of HOMA‐IR included the body mass index, and the serum levels of leptin (positive correlation) and adiponectin (negative correlation), but not that of TNFα and IL6. Only TNFα levels were correlated with the extent of histological injury (portal/periportal inflammation, P = 0.02). Conclusion: Whereas leptin and adiponectin contribute to IR, none of the adipocytokines accounted for the elevated IR in HCV‐infected subjects. The adipocytokines were not associated with histological features of chronic HCV infection except for TNFα which correlated with portal/periportal inflammation. HCV‐associated IR is most likely an adipocytokine‐independent effect of the virus to modulate insulin sensitivity. (HEPATOLOGY 2007;46:66–73.)

Genotype-Specific Interactions of Insulin Resistance, Steatosis, and Fibrosis in Chronic Hepatitis C

The interaction between insulin resistance (IR), steatosis and genotype to fibrosis in chronic hepatitis C virus (HCV) infection has not been comprehensively assessed. We hypothesized that IR is a key mediator for the development of both steatosis and fibrosis in 346 untreated, nondiabetic patients solely infected with either genotype 1 or 3. We examined for genotype‐specific interactions between IR, steatosis and fibrosis by performing subgroup analyses. Because cirrhosis is known to cause IR, we repeated the analysis in a cohort of 313 noncirrhotic HCV‐infected patients. We confirmed the impact of IR on fibrosis by analysis of 153 lean subjects in whom any effect of steatosis would be minimized. In HCV genotype 3 patients, increased steatosis was linked to high viral load (P = 0.001), and was not associated with fibrosis (P = 0.1). In contrast, body mass index (P = 0.04) and homeostasis model assessment of insulin resistance (HOMA‐IR) (P = 0.01) contributed directly to steatosis in HCV genotype 1. HOMA‐IR rather than steatosis was independently associated with fibrosis for both HCV genotype 1 (OR, 3.22; P = 0.02) and genotype 3 (OR, 3.17; P = 0.04). Exclusion of cirrhotic subjects did not alter the findings with respect to the greater contribution of IR compared to hepatic steatosis, as a predictor of fibrosis (P = 0.02). Genotype‐specific subgroup analyses did not alter this finding. The extent of HOMA‐IR remained significantly associated with fibrosis in lean patients, independent of the confounding effect of body mass index on IR (OR, 8.02; P = 0.003). Conclusion: IR is a major independent determinant of fibrosis in chronic HCV infection, regardless of the genotype and the severity of liver damage. (HEPATOLOGY 2008.)

Esophageal pneumatic dilation for postfundoplication dysphagia: safety, efficacy, and predictors of outcome

OBJECTIVE:Persistent dysphagia occurs in 5–10% of patients after fundoplication. The cause is obscure in most cases, and the management has not been well established. The aim of this study is to evaluate the clinical outcomes and the predictors of success for esophageal pneumatic dilations in patients with dysphagia after fundoplication.METHODS:We retrospectively reviewed 14 patients who underwent pneumatic dilation for persistent postfundoplication dysphagia. All patients had esophageal manometry before dilations.RESULTS:There were nine responders to pneumatic dilations (30–40-mm balloons). The nadir lower esophageal sphincter (LES) relaxation pressure was the only significant predictor for successful dilation and was higher among the responders than nonresponders (median 10 mm Hg vs 5 mm Hg). All six of 14 patients with nadir LES pressure ≥10 mm Hg had a good response. There was no significant difference in the LES basal pressure between the responders and nonresponders (median 20 mm Hg vs 12 mm Hg). The median distal peristaltic amplitude (74 mm Hg vs 69 mm Hg), percent of failed peristalsis (8% vs 45%), and ramp pressure (19 mm Hg vs 17 mm Hg) did not differ significantly between the responders and nonresponders. No perforations occurred.CONCLUSIONS:Pneumatic dilation is a reasonably safe and effective treatment for patients with postfundoplication dysphagia. Raised nadir LES relaxation pressure seems to be a useful predictor of successful outcome.

Prevalence of adenomas and sessile serrated adenomas in Chinese compared with Caucasians

Colonic adenomas and sessile serrated adenomas (SSA) are the most common premalignant polyps identified at colonoscopy. This study compares the prevalence of neoplastic polyps in Chinese and Caucasians in a general gastroenterology outpatient practice in Australia.