Janus P. Ong

Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease

BACKGROUND/AIMS The natural history of non-alcoholic fatty liver disease (NAFLD) remains to be defined. We conducted a study to determine the overall and liver-related mortality of NAFLD in the general US population. METHODS In this study, the Third National Health and Nutrition Examination Survey (NHANES III) and NHANES III-Linked Mortality File were used. Adjusted hazard ratios (HR) for overall and liver-related mortality were calculated for NAFLD using persons without liver disease as reference. Causes of death were determined. RESULTS After a median follow-up of 8.7 years, 80 persons with NAFLD and 1453 without liver disease died. Older age, male gender, non-Hispanic white race, lower educational level, lower income, higher BMI, presence of hypertension, diabetes mellitus, or metabolic syndrome were significantly (p<0.05) associated with overall mortality. Persons with NAFLD had higher overall mortality [HR 1.038 (95% CI 1.036-1.041), P<0.0001] and liver-related mortality [HR 9.32 (95% CI 9.21-9.43), P<0.0001]. Liver disease was the third leading cause of death among persons with NAFLD after cardiovascular disease and malignancy. CONCLUSIONS NAFLD is associated with higher overall and liver-related mortality in the general US population. Liver disease is a significant cause of death among persons with NAFLD.

Correlation between ammonia levels and the severity of hepatic encephalopathy

PURPOSE Because the correlation between ammonia levels and the severity of hepatic encephalopathy remains controversial, we prospectively evaluated the correlation in 121 consecutive patients with cirrhosis. METHODS The diagnosis of hepatic encephalopathy was based on clinical criteria, and the severity of hepatic encephalopathy was based on the West Haven Criteria for grading of mental status. Arterial and venous blood samples were obtained from each patient. Four types of ammonia measurements were analyzed: arterial and venous total ammonia, and arterial and venous partial pressure of ammonia. Spearman rank correlations (r(s)) were calculated. RESULTS Of the 121 patients, 30 (25%) had grade 0 encephalopathy (no signs or symptoms), 27 (22%) had grade 1, 23 (19%) had grade 2, 28 (23%) had grade 3, and 13 (11%) had grade 4 (the most severe signs and symptoms). Each of the four measures of ammonia increased with the severity of hepatic encephalopathy: arterial total ammonia (r(s) = 0.61, P < or = 0.001), venous total ammonia (r(s) = 0.56, P < or = 0.001), arterial partial pressure of ammonia (r(s) = 0.55, P < or = 0.001), and venous partial pressure of ammonia (r(s) = 0.52, P < or = 0.001). CONCLUSION Ammonia levels correlate with the severity of hepatic encephalopathy. Venous sampling is adequate for ammonia measurement. There appears to be no additional advantage of measuring the partial pressure of ammonia compared with total ammonia levels.

Predictors of Nonalcoholic Steatohepatitis and Advanced Fibrosis in Morbidly Obese Patients

Background: Nonalcoholic fatty liver disease (NAFLD) is a common form of chronic liver disease in the United States. It is commonly associated with the components of the metabolic syndrome including obesity. From the spectrum of NAFLD, only patients with nonalcoholic steatohepatitis (NASH) have been convincingly shown to have a potential for progression to cirrhosis. We report the prevalence of NAFLD and NASH as well as predictors of NASH and advanced fibrosis in morbidly obese patients. Methods: 212 consecutive patients who underwent bariatric surgery were enrolled in the study. A liver biopsy was performed at the time of the surgery. Causes of chronic liver disease other than NAFLD were excluded by clinical and laboratory evaluation. Results: The prevalence of NAFLD was 93%. Of those with NAFLD, 26% had NASH. 17 patients (9%) had advanced fibrosis (i.e., bridging fibrosis or cirrhosis). Male gender, AST, and type 2 diabetes mellitus were independently associated with NASH. Waistto-hip ratio, AST, and focal hepatocyte necrosis on liver biopsy were independently associated with advanced fibrosis. Interestingly, while AST was associated with NASH and advanced fibrosis, the majority of the patients with either NASH or advanced fibrosis had normal AST. Conclusions: NAFLD and NASH are very common in morbidly obese patients undergoing bariatric surgery. Features associated with the metabolic syndrome and liver cell injury are independently associated with either NASH or advanced fibrosis.

Non-alcoholic fatty liver disease: An overview

Non‐alcoholic fatty liver disease (NAFL) includes a spectrum of clinicopathological conditions with increasing prevalence in the developed world. Although steatosis alone seems to have a benign course, those patients with the diagnosis of non‐alcoholic steatohepatitis (NASH) can have a progressive course. Additionally, there is now evolving, indirect evidence that some of the patients with cryptogenic cirrhosis may be the result of ‘burned‐out’ NASH. Although NAFL and NASH are associated with insulin‐resistance syndrome, some patients with NAFL may have no obvious risk factors. Despite preliminary data from a number of pilot studies, no established therapies can be offered to patients with NASH. Over the next few years, a number of exciting research projects dealing with the epidemiology as well as the pathogenesis of NAFL are expected to be completed. It is anticipated that, through a better understanding of NAFL, more effective treatment protocols can be developed targeting only those patients with NASH that are at the highest risk for progression to cirrhosis and liver failure.

A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and some of its forms are progressive. This study describes the profiling of hepatic gene expression and serum protein content in patients with different subtypes of NAFLD. Liver biopsy specimens from 98 bariatric surgery patients were classified as normal, steatosis alone, steatosis with nonspecific inflammation, and nonalcoholic steatohepatitis (NASH). Microarray hybridizations were performed in triplicate and the microarray expression levels of a selected group of genes were confirmed using real‐time quantitative reverse‐transcriptase polymerase chain reaction. Serum protein profiles of the same patients were determined by SELDI‐TOF mass spectrometry. Of 98 obese patients, 91 were diagnosed with NAFLD (12 steatosis alone, 52 steatosis with nonspecific inflammation, and 27 NASH), and 7 patients without NAFLD served as obese controls. Each group of NAFLD patients was compared with the obese controls, and 22 genes with more than twofold differences in expression levels were revealed. Proteomics analyses were performed for the same group comparisons and revealed twelve significantly different protein peaks. In conclusion, this genomic/proteomic analysis suggests differential expression of several genes and protein peaks in patients within and across the forms of NAFLD. These findings may help clarify the pathogenesis of NAFLD and identify potential targets for therapeutic intervention. (HEPATOLOGY 2005;42:665–674.)

Obesity and non-alcoholic fatty liver disease in chronic hepatitis C.

Background Superimposed non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) may affect HCV-related fibrosis. We performed a study to determine the relationship between NAFLD and chronic hepatitis C. Methods One hundred and twenty patients with chronic hepatitis C and available liver biopsies were included. Baseline liver biopsies were read by 1 hepatopathologist using Metavir, as well as a fatty liver pathology protocol. Patients’ baseline clinical, demographic, and virologic data were associated with the extent of steatosis (>33% vs. ≤33%), the type of fatty liver (no steatosis vs. steatosis only vs. NASH), and the stage of fibrosis seen on the liver biopsy. Results Seventy percent of patients were men and 80% were white. The mean age was 47.48 ± 5.70 years, mean BMI was 29.01 ± 5.01 kg/m2, and mean waist to hip ratio (W/H) was 0.90 ± 0.08. Patients with higher grade of steatosis had higher BMI (32.83 ± 6.26 vs. 28.49 ± 4.62, P = 0.034), more likely to have genotype 3 (21.4% vs. 5.7%, P = 0.037) and advanced fibrosis (92.9% vs. 62.3%, P = 0.033) than those with lower grade of steatosis. Of these, only HCV-genotype 3 remained independently associated with higher grade of steatosis. When patients with superimposed NASH (n = 22) were compared with those with only steatosis (n = 49) and those without steatosis (n = 49), patients with superimposed NASH had more evidence of obesity (BMI: 30.64 ± 5.23 vs. 29.90 ± 5.35 vs. 27.33 ± 4.07, P = 0.008; W/H: 0.97 ± 0.06 vs. 0.91 ± 0.08 vs. 0.87 ± 0.07, P < 0.001), more commonly infected with HCV genotype 3 (14% vs. 12% vs. 0%, P = 0.036) and had more advanced fibrosis (95.5% vs. 75.5% vs. 42.9%, P < 0.001). Race, gender, and age did not affect extent of steatosis or presence of superimposed NASH. Conclusion In conclusion, markers of obesity (BMI and W/H) and HCV genotype 3 are associated with the extent of steatosis and type of fatty liver. Higher grade of steatosis and presence of superimposed NASH are both associated with advanced hepatic fibrosis.

Gene Expression of Leptin, Resistin, and Adiponectin in the White Adipose Tissue of Obese Patients with Non-Alcoholic Fatty Liver Disease and Insulin Resistance

Background: Adipose tissue is an active endocrine organ that secretes a variety of metabolically important substances including adipokines. These factors affect insulin sensitivity and may represent a link between obesity, insulin resistance, type 2 diabetes (DM), and nonalcoholic fatty liver disease (NAFLD). This study uses real-time polymerase chain reaction (PCR) quantification of mRNAs encoding adiponectin, leptin, and resistin on snap-frozen samples of intra-abdominal adipose tissue of morbidly obese patients undergoing bariatric surgery. Methods: Morbidly obese patients undergoing bariatric surgery were studied. Patients were classified into two groups: Group A (with insulin resistance) (N=11; glucose 149.84 ± 40.56 mg/dL; serum insulin 8.28 ± 3.52 μU/mL), and Group B (without insulin resistance) (N=10; glucose 102.2 ± 8.43 mg/dL; serum insulin 3.431 ± 1.162 μU/mL). Results: Adiponectin mRNA in intra-abdominal adipose tissue and serum adiponectin levels were significantly lower in Group A compared to Group B patients (P<0.016 and P<0.03, respectively). Although serum resistin was higher in Group A than in Group B patients (P<0.005), resistin gene expression was not different between the two groups. Finally, for leptin, neither serum level nor gene expression was different between the two groups. Serum adiponectin level was the only predictor of nonalcoholic steatohepatitis (NASH) in this study (P=0.024). Conclusions: Obese patients with insulin resistance have decreased serum adiponectin and increased serum resistin. Additionally, adiponectin gene expression is also decreased in the adipose tissue of these patients. This low level of adiponectin expression may predispose patients to the progressive form of NAFLD or NASH.

Hepatic gene expression in patients with obesity-related non-alcoholic steatohepatitis.

Abstract: Background: Non‐alcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disease. NAFLD includes a spectrum of clinicopathologic syndromes that includes non‐alcoholic steatohepatitis (NASH) that has potential for progression. The pathogenesis of NASH is poorly characterized.

Ursodeoxycholic Acid in the Prevention of Gallstone Formation after Bariatric Surgery: A Meta-analysis

BackgroundRapid weight loss increases risk for gallstone formation. Prophylactic cholecystectomy is difficult. Several small trials have shown that ursodeoxycholic acid (UDCA) may prevent gallstone formation after bariatric surgery. The aim of this study is to assess the efficacy and safety of UDCA in the prevention of gallstone formation after bariatric surgery.MethodsElectronic databases, including the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Australasian Medical Index, LILACS, and HERDIN, were searched. Reference lists of trials selected by the above electronic searching were also searched. Authors of the retrieved trials and pharmaceutical companies were also contacted for other trials, published and unpublished. A meta-analysis of all randomized, double-blind, placebo-controlled prospective trials comparing UDCA and placebo was performed.ResultsFive RCTs including 521 patients were assessed. Random effects meta-analysis showed a significant reduction of gallstone formation (RR 0.43, 95% confidence interval 0.22–0.83), with 8.8% of those taking UDCA developing gallstones compared to 27.7% for placebo. Although this meta-analysis is heterogeneous with I2 of 61.9%, the directions of the effect are all consistently in favor of UDCA (p = 0.01). A meta-analysis on the adverse effects could not be performed because the studies did not report them in a way to make the analysis possible.ConclusionsUDCA can prevent gallstone formation after bariatric surgery.

Obesity-related Differential Gene Expression in the Visceral Adipose Tissue

Background:This study investigates the expression patterns in human adipose tissue, and identifies genes that may be involved in the abnormal energy homeostasis. Methods: Subjects were prospectively recruited from morbidly obese patients undergoing bariatric surgery and from non-obese organ donors. Extensive clinical data and visceral fat specimens were obtained from each subject at the time of surgery. A group of 50 obese patients and 9 non-obese controls were selected for further study. Two custom two-color cDNA microarrays were produced with 40,173 human individual cDNA clones. Microarray experiments were performed for each sample, and a selected group of gene expression values were confirmed with real-time RT-PCR. Results: A comparison of gene expression profiles from obese and non-obese patients identified 1,208 genes with statistically significant differential expression between the 2 groups. Most prominent among these genes are multiple glycolysis enzyme encoding genes; others are involved in oxysterol biosynthesis and signaling, or are ATP-binding transporters and solute carriers. Conclusion: Differential gene expression in the adipose tissue of morbidly obese patients includes genes related to lipid and glucose metabolism, membrane transport, and genes promoting the cell cycle. These findings are a first step toward clarifying the molecular pathogenesis of obesity and identifying potential targets for therapeutic intervention.