James W. Maher

Increased Hepatic Synthesis and Dysregulation of Cholesterol Metabolism Is Associated with the Severity of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular and liver-related mortality. NAFLD is characterized by both triglyceride and free cholesterol (FC) accumulation without a corresponding increment in cholesterol esters. The aim of this study was to evaluate the expression of cholesterol metabolic genes in NAFLD and relate these to disease phenotype. NAFLD was associated with increased SREBP-2 maturation, HMG CoA reductase (HMGCR) expression and decreased phosphorylation of HMGCR. Cholesterol synthesis was increased as measured by the circulating desmosterol:cholesterol ratio. miR-34a, a microRNA increased in NAFLD, inhibited sirtuin-1 with downstream dephosphorylation of AMP kinase and HMGCR. Cholesterol ester hydrolase was increased while ACAT-2 remained unchanged. LDL receptor expression was significantly decreased and similar in NAFLD subjects on or off statins. HMGCR expression was correlated with FC, histologic severity of NAFLD and LDL-cholesterol. These data demonstrate dysregulated cholesterol metabolism in NAFLD which may contribute to disease severity and cardiovascular risks.

The Long-term Effects of Gastric Bypass on Vitamin D Metabolism

Objective:Alterations of the endocrine system in patients following Roux-en-Y gastric bypass (GBP) are poorly described and have prompted us to perform a longitudinal study of the effects of GBP on serum calcium, 25-hydroxy-vitamin-D (vitamin D), and parathyroid hormone (PTH). Methods:Prospectively collected data were compiled to determine how GBP affects serum calcium, vitamin D, and PTH. Student t test, Fisher exact test, or linear regression was used to determine significance. Results:Calcium, vitamin D, and PTH levels were drawn on 243 patients following GBP. Forty-one patients had long-limb bypass (LL-GBP), Roux >100 cm, and 202 had short-limb bypass (SL-GBP), Roux ≤100 cm. The mean (±SD) postoperative follow-up time was significantly longer in the LL-GBP group (5.7 ± 2.5 years) than the SL-GBP group (3.1 ± 3.6 years, P < 0.0001). When corrected for albumin levels, mean calcium was 9.3 mg/dL (range, 8.5–10.8 mg/dL), and no difference existed between LL-GBP and SL-GBP patients. For patients with low vitamin D levels (<8.9 ng/mL), 88.9% had elevated PTH (>65 pg/mL) and 58.0% of patients with normal vitamin D levels (≥8.9 ng/mL) had elevated PTH (P < 0.0001). In individuals with vitamin D levels <30 ng/mL, 55.1% (n = 103) had elevated PTH, and of those with vitamin D levels ≥30 ng/mL 28.5% (n = 16) had elevated PTH (P = 0.0007). Mean vitamin D levels were lower in patients who had undergone LL-GBP as opposed to those with SL-GBP, 16.8 ± 10.8 ng/mL versus 22.7 ± 11.1 ng/mL (P = 0.0022), and PTH was significantly higher in patients who had a LL-GBP (113.5 ± 88.0 pg/mL versus 74.5 ± 52.7 pg/mL, P = 0.0002). There was a linear decrease in vitamin D (P = 0.005) coupled with a linear increase in PTH (P < 0.0001) the longer patients were followed after GBP. Alkaline phosphatase levels were elevated in 40.3% of patients and correlated with PTH levels. Conclusion:Vitamin D deficiency and elevated PTH are common following GBP and progress over time. There is a significant incidence of secondary hyperparathyroidism in short-limb GBP patients, even those with vitamin D levels ≥30 ng/mL, suggesting selective Ca2+ malabsorption. Thus, calcium malabsorption is inherent to gastric bypass. Careful calcium and vitamin D supplementation and long-term screening are necessary to prevent deficiencies and the sequelae of secondary hyperparathyroidism.

A Decade of Change in Obesity Surgery

Background: The International (formerly National) Bariatric Surgery Registry began collecting data in January 1986. The aim of this study was to examine changes in the practice of surgical treatment of severe obesity that occurred during the decade of 1986 through 1995, as observed in the IBSR data. Methods: All data submitted to the IBSR during the decade were transferred to the IBM mainframe computer for analysis. Characteristics of operative type populations were compared over time using analysis of variance (ANOVA) for age, body mass index (BMI), operative weight and Chi-square (χ2) test for gender. Results: There has been a steady increase over the decade in mean patient weight. The operations used have changed from predominantly ‘simple’ operations to more frequent use of ‘complex’ operations. Within the categories of ‘simple’ and ‘complex’, an increase in the variety of operations occurred. As a group, patients with ‘simple’ operations have been heavier, more often male and public pay patients than those who have undergone ‘complex’ operations. One year weight loss was greater for Roux-en-Y gastric bypass (RGB) than vertical banded gastroplasty (VBG), but follow-up rates were too low to study the relative merits of the operations used. The reported incidence of operative mortality and serious complications (leak with peritonitis, abscess and pulmonary embolism) remained low. Conclusions: These observations and their implications can be summarized in three statements which relate to action for improved patient care in the beginning of the new century: (1) increasing weight of candidates for surgical treatment during this decade indicates the need for earlier use of operative treatment before irreversible complications of obesity can develop; (2) low risk of obesity surgery, decreasing postoperative hospital stay, and early weight control support the continued and increased use of surgical treatment; (3) continued widespread use of both ‘simple’ and ‘complex’ operations with increased modifications of standard RGB and VBG procedures emphasizes the need for standardized long-term data and analyses regarding both weight control and postoperative side-effects.

Laparoscopic mesh hiatoplasty for paraesophageal hernias and fundoplications: a critical analysis of the available literature.

BackgroundLittle grade A medical evidence exists to support the use of prosthetic material for hiatal closure. Therefore, the authors compiled and analyzed all the available literature to determine whether the use of prosthetic mesh in hiatoplasty for routine laparoscopic fundoplications (LF) or for the repair of large (>5 cm) paraesophageal hernias (PEH) would decrease recurrence.MethodsA literature search was performed using an inclusive list of relevant search terms via Medline/PubMed to identify papers (n = 19) describing the use of prosthetic material to repair the crura of patients undergoing laparoscopic PEH reduction, LF, or both.ResultsCase series (n = 5), retrospective reviews (n = 6), and prospective randomized (n = 4) and nonrandomized (n = 4) trials were identified. Laparoscopic procedures (n = 1,368) were performed for PEH, gastroesophageal reflux disease (GERD), hiatal hernia, or a combination of the three. Group A (n = 729) had primary suture repair of the crura, and group B (n = 639) had repair with either interposition of mesh to close the hiatus or onlay of prosthetic material after hiatal or crural closure. The use of mesh was associated with fewer recurrences than primary suture repair in both the LF and PEH groups. The mean follow-up period did not differ between the groups (20.7 months for group A vs. 19.2 months for group B). None of the papers cited any instance of prosthetic erosion into the gastrointestinal tract.ConclusionsThe current data tend to support the use of prosthetic materials for hiatal repair in both routine LF and the repair of large PEHs. Longer and more stringent follow-up evaluation is necessary to delineate better the safety profile of mesh hiatoplasty. Future randomized trials are needed to confirm that mesh repair is superior to simple crural closure.

Effect of Reversible Intermittent Intra-abdominal Vagal Nerve Blockade on Morbid Obesity The ReCharge Randomized Clinical Trial

IMPORTANCE Although conventional bariatric surgery results in weight loss, it does so with potential short-term and long-term morbidity. OBJECTIVE To evaluate the effectiveness and safety of intermittent, reversible vagal nerve blockade therapy for obesity treatment. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, sham-controlled clinical trial involving 239 participants who had a body mass index of 40 to 45 or 35 to 40 and 1 or more obesity-related condition was conducted at 10 sites in the United States and Australia between May and December 2011. The 12-month blinded portion of the 5-year study was completed in January 2013. INTERVENTIONS One hundred sixty-two patients received an active vagal nerve block device and 77 received a sham device. All participants received weight management education. MAIN OUTCOMES AND MEASURES The coprimary efficacy objectives were to determine whether the vagal nerve block was superior in mean percentage excess weight loss to sham by a 10-point margin with at least 55% of patients in the vagal block group achieving a 20% loss and 45% achieving a 25% loss. The primary safety objective was to determine whether the rate of serious adverse events related to device, procedure, or therapy in the vagal block group was less than 15%. RESULTS In the intent-to-treat analysis, the vagal nerve block group had a mean 24.4% excess weight loss (9.2% of their initial body weight loss) vs 15.9% excess weight loss (6.0% initial body weight loss) in the sham group. The mean difference in the percentage of the excess weight loss between groups was 8.5 percentage points (95% CI, 3.1-13.9), which did not meet the 10-point target (P = .71), although weight loss was statistically greater in the vagal nerve block group (P = .002 for treatment difference in a post hoc analysis). At 12 months, 52% of patients in the vagal nerve block group achieved 20% or more excess weight loss and 38% achieved 25% or more excess weight loss vs 32% in the sham group who achieved 20% or more loss and 23% who achieved 25% or more loss. The device, procedure, or therapy-related serious adverse event rate in the vagal nerve block group was 3.7% (95% CI, 1.4%-7.9%), significantly lower than the 15% goal. The adverse events more frequent in the vagal nerve block group were heartburn or dyspepsia and abdominal pain attributed to therapy; all were reported as mild or moderate in severity. CONCLUSION AND RELEVANCE Among patients with morbid obesity, the use of vagal nerve block therapy compared with a sham control device did not meet either of the prespecified coprimary efficacy objectives, although weight loss in the vagal block group was statistically greater than in the sham device group. The treatment was well tolerated, having met the primary safety objective. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01327976.

The effect of ursodiol on the efficacy and safety of extracorporeal shock-wave lithotripsy of gallstones: The dornier national biliary lithotripsy study

BACKGROUND In the treatment of gallstones with extracorporeal shock-wave lithotripsy, the bile acid ursodiol is administered to dissolve the gallstone fragments. We designed our study to determine the value of administering this agent. METHODS At 10 centers, 600 symptomatic patients with three or fewer radiolucent gallstones 5 to 30 mm in diameter, as visualized by oral cholecystography, were randomly assigned to receive ursodiol or placebo for six months, starting one week before lithotripsy. RESULTS The stones were fragmented in 97 percent of all patients, and the fragments were less than or equal to 5 mm in diameter in 46.8 percent. On the basis of an intention-to-treat analysis of all 600 patients, 21 percent receiving ursodiol and 9 percent receiving placebo (P less than 0.0001) had gallbladders that were free of stones after six months. Among those with completely radiolucent solitary stones less than 20 mm in diameter, 35 percent of the patients receiving ursodiol and 18 percent of those receiving placebo (P less than 0.001) were free of stones after six months. Biliary pain, usually mild, occurred in 73 percent of all patients but in only 13 percent of those who were free of stones after three and six months (P less than 0.01). There were few adverse events. Only diarrhea occurred with a significantly different frequency in the two groups: 32.6 percent were affected in the ursodiol group, as compared with 24.7 percent in the placebo group (P less than 0.04). Severe biliary pain occurred in 1.5 percent of all patients, acute cholecystitis in 1.0 percent, and acute pancreatitis in 1.5 percent; endoscopic sphincterotomy was performed in 0.5 percent, and cholecystectomy in 2.5 percent. CONCLUSIONS Extracorporeal shock-wave lithotripsy with ursodiol was more effective than lithotripsy alone for the treatment of symptomatic gallstones, and equally safe. Treatment was more effective for solitary than multiple stones, radiolucent than slightly calcified stones, and smaller than larger stones.

Vertical gastroplasty : Evolution of vertical banded gastroplasty

Abstract. The objective of this paper is to summarize the goals, technical requirements, advantages, and potential risks of gastroplasty for treatment of severe obesity. Gastroplasty is preferred to more complex operations, as it preserves normal digestion and absorption and avoids complications that are peculiar to exclusion operations. The medical literature and a 30-year experience at the University of Iowa Hospitals and Clinics (UIHC) provides an overview of vertical banded gastroplasty (VBG) evolution. Preliminary 10-year results with the VBG technique currently used at UIHC are included. At UIHC the VBG is preferred to other gastroplasties because it provides weight control that extends for at least 10 years and the required objective, intraoperative quality control required for a low rate of reoperation. It is recommended that modifications of the operative technique not be attempted until a surgeon has had experience with the standardized operation—and then only under a carefully designed protocol. Realistic goals for surgery and criteria of success influence the choice of operation and the optimum, lifelong risk/benefit ratio. In conclusion, VBG is a safe, long-term effective operation for severe obesity with advantages over complex operations and more restrictive simple operations.

Reflex laryngospasm induced by stimulation of distal esophageal afferents

Distal esophageal sensory nerves were stimulated in 17 anesthetized dogs divided into three age groups to determine the laryngeal, cardiovascular, and respiratory effects. Group I puppies were 5 to 6 weeks of age, group II puppies were 8 to 19 weeks of age, and group III animals were adult dogs. Marked laryngeal adductor activity and laryngospasm were observed in group II puppies, while no or minimal laryngeal adduction was seen in younger puppies and adult dogs. Mean arterial pressure and heart rate increased significantly in groups II and III (P<.005) but remained unchanged in group I animals (P>.4). This response is distinctly different from the laryngeal chemoreflex because central apnea, hypotension, and bradycardia were absent. The afferent limb of the response is mediated by the vagus nerve as bilateral transthoracic truncal vagotomy eliminated the reflex. The laryngeal response observed following stimulation of distal esophageal afferent fibers may be important in the mechanism of apparent life‐threatening events (ALTEs) and the sudden infant death syndrome (SIDS) associated with gastroesophageal reflux disease.

Four Hundred Fifty Consecutive Laparoscopic Roux-en-Y Gastric Bypasses with No Mortality and Declining Leak Rates and Lengths of Stay in a Bariatric Training Program

BACKGROUND We reviewed our obesity surgery database for 2 experienced bariatric surgeons since their last patient death in October 2003 through July 2007. STUDY DESIGN Data on all patients undergoing planned laparoscopic Roux-en-Y gastric bypass (L-GBP) by the two attending bariatric surgeons at the Medical College of Virginia Hospitals were reviewed. The operations were performed by fellows in minimally invasive surgery, assisted by the 2 attending physicians in more than 90% of patients. Surgical technique included a handsewn imbrication of a gastrojejejunostomy and jejunojejunostomy, each performed with a linear stapler. Routine sampling of a juxtaanastamotic drain for amylase levels was substituted for routine upper gastrointestinal contrast studies during the study period. RESULTS All patients, except those who had earlier extensive upper abdominal surgery in that time period, were offered a laparoscopic approach (5.7% were converted to open procedures). The mean (+/- SD) age was 42.4+/-11 years; body mass index was 49.5+/-9 kg/m(2). Women represented 80.5% of patients. The leak rate declined from 9.7% in 2004 to 2.0% in 2006 (p < 0.05, chi-square test); there have been no leaks in any patient since July 2006, including the 40 patients in 2007. Hospital length of stay declined from 4.7+/-5.7 days in 2004 to 2.9+/-3.3 days in 2006 (p < 0.05, Wilcoxon rank test). At 1-year followup, 270 patients had lost 66.1%+/-17% of initial excess weight, which was similar to that in our open gastric bypasses. Comorbid conditions improved or resolved in 67.6% of patients with diabetes, 56.1% of those with hypertension, 75% of those with sleep apnea, 87.8% of those with urinary stress incontinence, 95.9% of those with gastroesophageal reflux disease, and in 100% of those with stasis ulcers. Overall complication rates of wound infection (1.5%), incisional hernia (1.7%), internal hernia (0.2%), and intestinal obstruction (1.7%) were low. CONCLUSIONS Results for laparoscopic Roux-en-Y gastric bypass improve with experience and can be taught in an academic training program, with low morbidity and mortality. Routine postoperative upper gastrointestinal contrast studies are unnecessary and may lengthen hospital stay.

Prospective investigation of complications, reoperations, and sustained weight loss with an adjustable gastric banding device for treatment of morbid obesity☆☆☆

The purpose of this study was to determine prospectively the safety and efficacy of an adjustable silicone gastric band and reservoir system for the treatment of morbid obesity. Between 1992 and 1995, forty primary procedures were performed. Twenty-six females and 14 males entered the study. The mean age of the subjects was 34 years (range 19 to 51 years). Mean body mass index was 50 kg/m 2 (range 39 to 75 kg/m2). There were no deaths. Mean body mass index (0in kg/m 2) at follow-up visits was 38.4 at I year, 38.0 at 2 years, 40.2 at 3 years, and 40.4 at 4 years. These decreases were significant at P <0.001. Thirty-two reoperations (12 intra-abdominal procedures and 20 abdominal wall procedures) have been necessary to maintain efficacy or correct complications. At the four-year interval, the reoperation rate of 80% was unsatisfactory. The excess weight loss has been 41% for those subjects who have an intact gastric band system and continue in the study. Improvements to the implantable band and/or operative technique must be implemented and studied long term if this procedure is to become an accepted surgical treatment for severe obesity.