Safety and efficacy of bariatric surgery in patients with advanced fibrosis.

BACKGROUND: Bariatric surgery is performed safely in non-alcoholic fatty liver disease (NAFLD) patients with minimal fibrosis (stage 1-2). However, the safety and potential benefits of bariatric surgery for NAFLD with advanced fibrosis (stage 3-4) remain unclear. This study was designed to compare the safety and efficacy of bariatric surgery in patients with biopsy proven advanced fibrosis to those with minimal fibrosis. METHODS: All patients who underwent bariatric surgery between 2005 and 2014 and had evidence of NAFLD with fibrosis score 3-4 (advanced fibrosis) based on the staging system defined by Kleiner et al. on intraoperative liver biopsy were included and compared with patients who had fibrosis score 1-2 (minimal fibrosis). The groups were compared for length of hospital stay after bariatric surgery and incidence of postoperative complications over a follow-up period of 1 year. An improvement in hepatic function tests before and 1 year after surgery was used as a parameter to evaluate for NAFLD improvement. RESULTS: Ninety-nine patients with F3-4 (group 1) and 198 patients with F1-2 (group 2) were included. Mean age (51.9 vs 50.1 years) and body mass index (46.4 vs 46.5 kg m-2) were similar in the two groups. Median serum aspartate aminotransferase (43 vs 30 U l-1; normal 10-40 U l-1) and alanine aminotransferase (40.5 vs 34 U l-1; normal 10-50 U l-1) were significantly higher in group 1 and improved 1 year after surgery. Median length of hospital stay after surgery was higher in group 1 than that in group 2 (4 days vs 3 days; P-value=0.002). The proportion of patients developing postoperative complications over 1 year was similar in both groups (36.4% vs 32.8%; P-value=0.54). CONCLUSIONS: Advanced fibrosis does not increase the risk of developing postoperative complications in medically optimized patients undergoing bariatric surgery. Improvement in serum transaminase levels suggests a reduction in hepatic necroinflammatory activity following bariatric surgery.

Liver Transplantation for Hepatocellular Carcinoma among African Americans in the United States.

BACKGROUND: There is increased prevalence of hepatocellular carcinoma (HCC) among African Americans (AA). Multicenter studies have shown advanced presentation, underutilization of treatment and decreased survival following liver transplantation (LT) among AA. However outcomes from single centers are not well reported. OBJECTIVE: To determine the outcome of AA undergoing LT for HCC at Cleveland Clinic, Cleveland, Ohio, between May 2007 and December 2009. METHODS: 245 consecutive patients undergoing evaluation and treatment for HCC within the mentioned time frame were studied, retrospectively. RESULTS: 80% of patients were male, 75.5% were Caucasian, 16.7% were AA and 7.8% were other ethnic groups. Compared to other ethnicities, AA subjects with HCC were more commonly female and were more likely to have hepatitis C virus (HCV) (83% vs. 51%, p<0.001). There were higher occurrence of HCV genotype 1 among AA compared to others among patients with this information (100% vs. 65%, p<0.001). In contrast to previous reports, there was no significant difference between the groups in terms of clinical presentation or management. 27% of AA underwent liver transplantation compared to 28% of the rest (p=0.88). Of the 68 patients who had LT, 9% died with no difference in post-LT survival between the two groups. CONCLUSIONS: HCV (and genotype 1) is a significant risk factor for HCC in the AA population. LT results in similar survival compared to other ethnicities. AA patients with HCC benefit equally from LT compared to other ethnicities.

Use of tegaserod along with polyethylene glycol electrolyte solution for colonoscopy bowel preparation: a prospective, randomized, double-blind, placebo-controlled study.

BACKGROUND: Polyethylene glycol electrolyte solution (PEG-EL) used for colonoscopy preparation is not well tolerated by several patients. A significant number of patients have inadequate bowel preparation despite taking PEG-EL. AIMS: To determine the effect of prokinetic agent, tegaserod when given in addition to PEG-EL on patient tolerance, quality of colonic preparation and adverse side effects experienced. METHODS: In this prospective, randomized, placebo-controlled, double-blind study, a total of 130 patients scheduled for colonoscopy were enrolled. They were instructed to take three pills of either tegaserod 6 mg each or placebo (one pill twice on the day prior to and third pill in the morning on the day of colonoscopy) in addition to standard 4L of PEG-EL in the evening prior to the day of colonoscopy. Patient tolerance of preparation, quality of bowel preparation, overall satisfaction and adverse side effects were compared between the two groups. RESULTS: Fifty-five patients in placebo group and 58 patients in tegaserod group completed the study. There was no difference between the two groups in the tolerance of preparation, quality of bowel preparation, overall satisfaction and the side effects. CONCLUSION: Addition of tegaserod to polyethylene glycol electrolyte solution during colonoscopy preparation does not improve patient tolerance, quality of colonic preparation or the adverse side effects.

Nonalcoholic fatty liver disease: a feature of the metabolic syndrome.

Insulin sensitivity (euglycemic clamp, insulin infusion rate: 40 mU. m(-2). min(-1)) was studied in 30 subjects with biopsy-proven nonalcoholic fatty liver disease (NAFLD), normal glucose tolerance, and a BMI <30 kg/m(2). Of those 30 subjects, 9 had pure fatty liver and 21 had evidence of steatohepatitis. In addition, 10 patients with type 2 diabetes under good metabolic control and 10 healthy subjects were studied. Most NAFLD patients had central fat accumulation, increased triglycerides and uric acid, and low HDL cholesterol, irrespective of BMI. Glucose disposal during the clamp was reduced by nearly 50% in NAFLD patients, as well as in patients with normal body weight, to an extent similar to that of the type 2 diabetic patients. Basal free fatty acids were increased, whereas insulin-mediated suppression of lipolysis was less effective (-69% in NAFLD vs. -84% in control subjects; P = 0.003). Postabsorptive hepatic glucose production (HGP), measured by [6,6-(2)H(2)]glucose, was normal. In response to insulin infusion, HGP decreased by only 63% of basal in NAFLD vs. 84% in control subjects (P = 0.002). Compared with type 2 diabetic patients, NAFLD patients were characterized by lower basal HGP, but with similarly reduced insulin-mediated suppression of HGP. There was laboratory evidence of iron overload in many NAFLD patients, but clinical, histological, and biochemical data (including insulin sensitivity) were not correlated with iron status. Four subjects were heterozygous for mutation His63Asp of the HFE gene of familiar hemochromatosis. We concluded that NAFLD, in the presence of normoglycemia and normal or moderately increased body weight, is characterized by clinical and laboratory data similar to those found in diabetes and obesity. NAFLD may be considered an additional feature of the metabolic syndrome, with specific hepatic insulin resistance.

Gender differences in leucine, but not lysine, kinetics.

There is a controversy in the literature as to the effects of gender on leucine kinetics. Two research groups found that men oxidize more leucine during exercise, whereas another group showed no gender effects. The purpose of our study was to examine the effects of gender on leucine and, for comparison purposes, lysine kinetics. Our subjects (n = 14) were seven matched pairs of men and women selected for their exercise habits and age. After 1 wk of a standardized diet, they exercised at 50% of maximal O(2) uptake for 1 h. There was an effect of exercise in both genders: an increased leucine oxidation and an attenuation in nonoxidative leucine disposal compared with rest (P < 0.05). Furthermore, our study confirms that there are gender differences in leucine, but not lysine, kinetics. Men had a higher rate of leucine oxidation and a lower rate of nonoxidative leucine disposal during exercise (P < 0.05). For women, a larger proportion of their exercise energy needs came from fat; for men, a greater fraction came from carbohydrate (P < 0.05). We conclude that female exercisers rely to a greater extent on fat as an energy source, thereby using less carbohydrate, amino acid, and protein as a fuel source.

Clinical features and natural history of nonalcoholic steatosis syndromes.

Nonalcoholic steatohepatitis, along with other forms of nonalcoholic fatty liver disease, is a chronic liver disease that is attracting increasing significance. It is a clinicopathologic syndrome that was originally described in obese, diabetic females who denied alcohol use but in whom the hepatic histology was consistent with alcoholic hepatitis. This typical patient profile has been expanded and is now recognized to occur even in normal weight males without overt abnormalities in carbohydrate metabolism. Although originally believed to be a benign clinical entity, nonalcoholic steatohepatitis is now recognized as a cause of progressive fibrotic liver disease with adverse clinical sequelae. It is important to emphasize that nonalcoholic steatohepatitis is best considered one type of a larger spectrum of nonalcoholic fatty liver disease that is a consequence of insulin resistance and ranges from fat alone to fat plus inflammation, fat plus ballooning degeneration, and nonalcoholic steatohepatitis, the latter being the most serious form. As with any disease, the clinical importance of nonalcoholic steatohepatitis is related to its prevalence and natural history. Recent studies using different methodologies indicate that in the general population the prevalence of fatty liver and nonalcoholic steatohepatitis is approximately 20% and 3%, respectively. These prevalence rates are increased in certain subpopulations such as obesity and type II diabetes. Of greater concern is the recognition that cirrhosis and liver-related deaths occur in approximately 20% and 8% of these patients, respectively, over a 10-year period. Risk factors for these adverse clinical symptoms include patients older than the age of 45, the presence of diabetes or obesity, an aspartate aminotransferase/alanine aminotransferase ratio > 1 and hepatic histology. However, a number of important unresolved issues must be clarified before the true natural history of this disease can be fully understood.

Relationship between leucine oxidation and oxygen consumption during steady-state exercise.

PURPOSE: The purpose of this study was to assess the relationship between whole-body leucine oxidation and oxygen consumption during steady-state exercise. Our hypothesis was that leucine oxidation will be responsive to increased whole-body energy needs. METHODS: Sixteen healthy individuals (7 women and 9 men) were infused with a stable isotope of leucine and, for comparison purposes, lysine during 60 min of moderate-intensity exercise. RESULTS: Leucine oxidation was increased (P < 0.05) and nonoxidative leucine disposal was decreased (P < 0.05), whereas leucine and lysine rate of appearance remained unchanged (P = NS) during exercise. Linear regression analysis indicated a modest relationship between leucine oxidation and steady-state oxygen consumption (R = 0.69; P < 0.003) during steady-state exercise. The coefficient of determination (R(2) = 0.49) indicates that approximately half of the variance in whole-body leucine oxidation during exercise can be explained by whole-body oxygen consumption. CONCLUSION: In a statistically appropriate sample size of humans whose dietary intake was controlled, the whole-body rate of leucine oxidation during exercise was only partially influenced by energy demands.

An intronic splicing enhancer binds U1 snRNPs to enhance splicing and select 5' splice sites.

Intronic G triplets are frequently located adjacent to 5' splice sites in vertebrate pre-mRNAs and have been correlated with splicing efficiency and specificity via a mechanism that activates upstream 5' splice sites in exons containing duplicated sites (26). Using an intron dependent upon G triplets for maximal activity and 5' splice site specificity, we determined that these elements bind U1 snRNPs via base pairing with U1 RNA. This interaction is novel in that it uses nucleotides 8 to 10 of U1 RNA and is independent of nucleotides 1 to 7. In vivo functionality of base pairing was documented by restoring activity and specificity to mutated G triplets through compensating U1 RNA mutations. We suggest that the G-rich region near vertebrate 5' splice sites promotes accurate splice site recognition by recruiting the U1 snRNP.

Nutritional effects of alcoholism.

Alcohol is the most frequently used drug worldwide and remains a socially acceptable hepatotoxin. Although the toxic effects of alcohol on various organs (liver, pancreas, heart, and intestine) are well recognized, the role of alcohol in overall energy and protein metabolism is less well understood. In particular, the efficiency of alcohol as a source of calories and as a substrate for energy production appears to be influenced by the amount of both alcohol and fat consumption as well as by gender. The relationship between alcohol intake and body weight is complex, but it is a clinical dilemma with important nutritional implications for weight management in addition to specific organ toxicity.

Leptin and the gastrointestinal tract.

The discovery of leptin in 1990 was the culmination of earlier work which recognized that communication between the adipocyte and the hypothalamus was important in maintaining body weight. Leptin, which is a 16 kilodalton protein-encoded by the OB gene, is involved in the regulation of food intake, body composition, and energy expenditure through a central feedback mechanism. Initially thought to be adipocyte-specific, the OB gene, as well as the leptin receptor, have been found in a variety of other tissues. Relevant to this review, the leptin gene and its receptor have been identified in the stomach, intestine, liver, and pancreas. Recent data also suggest that leptin may act locally within the gastrointestinal tract to influence intestinal function. This review emphasizes the concept that leptin may be a new gastrointestinal hormone and the need to expand the focus of leptin research to include all phases of weight maintenance, such as nutrient absorption and utilization, in addition to food intake.

Association of nonalcoholic fatty liver disease with insulin resistance.

BACKGROUND AND PURPOSE: Nonalcoholic fatty liver disease is frequently associated with type 2 diabetes mellitus, obesity, and dyslipidemia, but some patients have normal glucose tolerance or normal weight. We tested the hypothesis that there is an association between nonalcoholic fatty liver disease and insulin resistance that is independent of diabetes and obesity. SUBJECTS AND METHODS: We measured anthropometric and metabolic variables in 46 patients with chronically elevated serum aminotransferase levels, "bright liver" on ultrasound scan, and normal glucose tolerance. Indexes of insulin resistance and secretion were determined using the homeostasis model assessment method. They were compared with 92 normal subjects who were matched for age and sex. RESULTS: Patients with nonalcoholic fatty liver disease were characterized by fasting and glucose-induced hyperinsulinemia, insulin resistance, postload hypoglycemia, and hypertriglyceridemia. Insulin resistance [odds ratio (OR) = 15 per percent increase, 95% confidence interval (CI): 3.0 to 70], fasting triglyceride level (OR = 3.1 per mmol/liter increase, 95% CI: 1.1 to 8.9), 180-minute blood glucose level (OR = 4.3 per mmol/ liter decrease, 95% CI: 1.6 to 12), and average insulin concentration in response to oral glucose (OR = 3.0 per 100 pmol/liter increase, 95% CI: 1.5 to 6.2) were independently associated with nonalcoholic fatty liver disease. The exclusion of overweight and obese subjects did not change the results. CONCLUSION: Nonalcoholic fatty liver disease is associated with insulin resistance and hyperinsulinemia even in lean subjects with normal glucose tolerance. Genetic factors that reduce insulin sensitivity and increase serum triglyceride levels may be responsible for its development.

Hepatic iron and nonalcoholic fatty liver disease.

Increased iron is suspected to enhance hepatic injury associated with nonalcoholic fatty liver disease (NAFL). We evaluated the impact of iron accumulation on the outcome of NAFL. Patients with NAFL were identified from our database. Twenty-two clinicodemographic and 19 pathological features were available for each patient. Histological staining (Perls' Prussian blue), hepatic iron concentration (HIC), and hepatic iron index (HII) were determined. Data on follow-up, mortality, and cause of death were analyzed. In 65 patients with available liver biopsy blocks, HIC and HII were 1,171 +/- 717 microgram/g dry weight and 0.43 +/- 0.30 micromol/g/yr, respectively. Males had more iron accumulation (HIC: 1,514 +/- 836 vs. 859 +/- 389, P =.0001; and HII: 0.58 +/- 0.35 vs. 0.29 +/- 0.16, P =.0001). In type II diabetics, both HIC (977 +/- 769 vs. 1,301 +/- 659; P <.05) and HII (0.30 +/- 0.23 vs. 0.52 +/- 0.32; P <.05) were lower. Iron accumulation was not related to other variables analyzed. Increased iron was not seen in those with higher grades of fibrosis or other pathological features associated with the aggressive form of NAFL (hepatocyte necrosis, fibrosis, ballooning degeneration, and Mallory hyaline). Iron accumulation was not associated with increased overall mortality, liver-related mortality, or development of cirrhosis. In summary, in most patients with NAFL, significant iron accumulation is not seen. Additionally, in our series of patients with NAFL, iron is not associated with poor clinical or pathological outcomes.

A continuous quality improvement initiative reduces inappropriate prescribing of prophylactic antibiotics for endoscopic procedures.

OBJECTIVE: Despite the availability of guidelines, most gastroenterologists do not administer prophylactic antibiotics appropriately to patients having endoscopic procedures. In 1994 we recognized that in our endoscopy unit, many patients were receiving antibiotics without proper indication. We devised a continuous quality improvement initiative to analyze and improve this problem. METHODS: Divisional guidelines for the appropriate administration of prophylactic antibiotics for endoscopy were drawn up in 1995. By retrospective analysis of our comprehensive endoscopy database we compared the rate of prophylactic antibiotic administration, and the proportion of antibiotics that were indicated before and after adoption of the divisional guidelines. RESULTS: A total of 1427 endoscopic procedures were done during a 6-month period in 1994 (before adoption of guidelines). Of these, 55 (3.85%) received antibiotics. In a 6-month period in 1996 after adoption of guidelines, 1452 procedures were performed and 29 of these (1.99%) received antibiotics. The odds ratio for receiving antibiotics appropriately in 1996, compared with 1994, was 3.4 (chi2 p = 0.016). Given an annual volume of 2900 procedures in our endoscopy unit, approximately 54 patients will avoid unnecessary antibiotics, yielding a cost saving of $1128 per year. CONCLUSIONS: A divisional continuous quality improvement initiative on antibiotic prophylaxis for endoscopy significantly reduced the proportion of patients receiving antibiotics unnecessarily. This quality improvement initiative enhanced the quality of care for patients having endoscopy and yielded a small cost saving. These improvements were achieved with minimal effort and cost to the division.

Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.

BACKGROUND & AIMS: The spectrum of nonalcoholic fatty liver disease ranges from fatty liver alone to nonalcoholic steatohepatitis. Most previous studies have short follow-up and have not carefully delineated different histological types when determining clinical outcomes. The aim of this study was to compare clinical characteristics and outcomes of patients with different types of nonalcoholic fatty liver. METHODS: All liver biopsy specimens from 1979 to 1987 with fat accumulation were assessed for inflammation, ballooning degeneration, Mallory hyaline, and fibrosis. Biopsy specimens were also assessed for histological iron and hepatitis C RNA. Outcomes were cirrhosis, mortality, and liver-related mortality. RESULTS: Of 772 liver biopsy specimens, complete data were available in 132 patients. Fatty liver (type 1) did not differ from the other three types combined with respect to gender, race, age, or obesity. Cirrhosis was more common in the other types combined (22%) than fatty liver alone (4%; P