Bariatric Surgery for Monogenic Non-syndromic and Syndromic Obesity Disorders.

PURPOSE OF REVIEW: The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders). Therefore, this review aims to elucidate the role of bariatric surgery in the treatment of genetic obesity. RECENT FINDINGS: In monogenic non-syndromic obesity, an underlying genetic defect seems to be the most important factor determining the efficacy of bariatric surgery. In syndromic obesity, bariatric surgery result data are scarce, and even though some promising follow-up results have been reported, caution is required as patients with more severe behavioral and developmental disorders might have poorer outcomes. There is limited evidence in support of bariatric surgery as a treatment option for genetic obesity disorders; hence, no strong statements can be made regarding the efficacy and safety of these procedures for these patients. However, considering that patients with genetic obesity often present with life-threatening obesity-related comorbidities, we believe that bariatric surgery could be considered a last-resort treatment option in selected patients.

Genetic obesity: next-generation sequencing results of 1230 patients with obesity.

BACKGROUND: Obesity is a global and severe health problem. Due to genetic heterogeneity, the identification of genetic defects in patients with obesity can be time consuming and costly. Therefore, we developed a custom diagnostic targeted next-generation sequencing (NGS)-based analysis to simultaneously identify mutations in 52 obesity-related genes. The aim of this study was to assess the diagnostic yield of this approach in patients with suspected genetic obesity. METHODS: DNA of 1230 patients with obesity (median BMI adults 43.6 kg/m2; median body mass index-SD children +3.4 SD) was analysed in the genome diagnostics section of the Department of Genetics of the UMC Utrecht (The Netherlands) by targeted analysis of 52 obesity-related genes. RESULTS: In 48 patients pathogenic mutations confirming the clinical diagnosis were detected. The majority of these were observed in the MC4R gene (18/48). In an additional 67 patients a probable pathogenic mutation was identified, necessitating further analysis to confirm the clinical relevance. CONCLUSIONS: NGS-based gene panel analysis in patients with obesity led to a definitive diagnosis of a genetic obesity disorder in 3.9% of obese probands, and a possible diagnosis in an additional 5.4% of obese probands. The highest yield was achieved in a selected paediatric subgroup, establishing a definitive diagnosis in 12 out of 164 children with severe early onset obesity (7.3%). These findings give a realistic insight in the diagnostic yield of genetic testing for patients with obesity and could help these patients to receive (future) personalised treatment.

Long-Term Weight Outcome After Bariatric Surgery in Patients with Melanocortin-4 Receptor Gene Variants: a Case-Control Study of 105 Patients.

INTRODUCTION: Pathogenic heterozygous MC4R variants are associated with hyperphagia and variable degrees of obesity. Several research groups have reported short-term weight loss outcomes after bariatric surgery in a few patients with MC4R variants, but lack of longer-term data prevents evidence-based clinical decision-making. MATERIALS AND METHODS: Bariatric surgery patients with heterozygous (likely) pathogenic MC4R variants, from three collaborating centers in the Netherlands, France, and the UK, were compared to matched controls (matched 2:1 for age, sex, preoperative BMI, surgical procedure, and diabetes mellitus, but without MC4R mutations). Weight loss and regain outcomes up to 6 years of follow-up were compared. RESULTS: At 60 months of follow-up after RYGB, cases with MC4R variants showed weight regain with a mean of 12.8% (± 10.4 SD) total weight loss (TWL) from nadir, compared to 7.9% (± 10.5 SD) in the controls (p = 0.062). Among patients receiving SG, the cases with MC4R variants experienced inferior weight loss (22.6% TWL) during the first year of follow-up compared to the controls (29.9% TWL) (p = 0.010). CONCLUSIONS: This multicenter study reveals inferior mid-term weight outcomes of cases with MC4R variants after SG, compared to RYGB. Since adequate weight loss outcomes were observed after RYGB, this procedure would appear to be an appropriate surgical approach for this group. However, the pattern of weight regain seen in cases with MC4R variants after both RYGB and SG highlights the need for pro-active lifelong management to prevent relapse, as well as careful expectation management.

Optimizing Multivitamin Supplementation for Sleeve Gastrectomy Patients.

PURPOSE: Micronutrient deficiencies are frequently reported after sleeve gastrectomy (SG), and therefore lifelong daily multivitamin supplementation is highly recommended. Based on literature and the results of a previous randomized controlled trial, a specialized multivitamin supplement for SG patients was further optimized (WLS Optimum 2.0, FitForMe). The present study reports on its short-term effectiveness. MATERIALS AND METHODS: An open-label study was performed in which 76 patients were included to receive WLS Optimum 2.0 for 12 months (Opt 2.0 group). This group was compared with a group of 75 patients that had received WLS Optimum 1.0 for 12 months during a previous study (Opt 1.0 group). RESULTS: Intention-to-treat analysis (Opt 1.0, n = 69; Opt 2.0, n = 75) showed higher serum levels of vitamin B12, vitamin B6, and zinc, and a lower prevalence of deficiencies for vitamin B12 and phosphate in the Opt 2.0 group. MCV and serum folic acid levels were higher in the Opt 1.0 group. Over the 12-month study period, mean increase in serum levels of phosphate, vitamin B6, and zinc was higher in the Opt 2.0 group, and MCV and serum vitamin D levels increased more in the Opt 1.0 group. CONCLUSION: The present study showed that the use of a specialized multivitamin supplement for SG patients is effective at preventing deficiencies for most vitamins and minerals, specifically in compliant patients. However, a strict follow-up regime remains necessary to monitor nutritional status and to improve patient compliance.

An Extended Pouch in a Roux-En-Y Gastric Bypass Reduces Weight Regain: 3-Year Results of a Randomized Controlled Trial.

BACKGROUND: Although the Roux-en-Y gastric bypass (RYGB) is considered a standard procedure, many variations exist in the basic design. In order to achieve more pronounced and sustainable results after RYGB, factors such as diameter of the gastroenterostomy, limb length, and pouch size are gripping points for improvement of design. Extending the pouch could improve results by altering food passage through the pouch. OBJECTIVE: The aim of this randomized controlled trial was to evaluate the effect of an extended pouch RYGB (EP-GB) and standard pouch RYGB (S-GB). METHODS: In total, 132 patients were randomized in two groups: 68 patients received an EP-GB (pouch length 10 cm) and 64 a S-GB (pouch length 5 cm). Subsequently, weight loss, remission of comorbidities, nutritional status, complications, quality of life, and GERD-symptoms were assessed during a follow-up of 3 years. RESULTS: During the first 2 years of follow-up, no significant differences in terms of weight loss were observed. In the third year of follow-up, the S-GB group regained 3 kg, while in the EP-GB group no weight regain was observed. The mean TBWL after 36 months in the EP-GB group was 31% versus 27% in the S-GB group (p = 0.023). Additionally, besides a better remission rate of hypertension in the EP-GB group, no differences in complications, quality of life, and GERD-symptoms were found. CONCLUSION: Creation of an extended gastric pouch is a safe and effective modification in RYGB design. An EP-GB improves mid-term weight loss, potentially driven by a lower occurrence of weight regain.

Functional Analysis of the SIM1 Variant p.G715V in 2 Patients With Obesity.

CONTEXT: Single-minded homologue 1 (SIM1) is a transcription factor with several physiological and developmental functions. Haploinsufficiency of SIM1 is associated with early-onset obesity with or without Prader-Willi-like (PWL) features and may exhibit incomplete penetrance. CASE DESCRIPTION: Next-generation sequencing was performed for 2 male patients with obesity, including 1 man presenting with intellectual disability (ID), body mass index (BMI) of 47.4, and impulse-control disorder, and the other man with early obesity (BMI of 36); sequencing revealed a missense variant in SIM1 (c.2144G>T; p.G715V) in both individuals. Previous studies have identified several disease-associated variants that fall near the p.G715V variant within the C-terminal domain of SIM1. We examined p.G715V variant stability and activity in a doxycycline-inducible stable cell line transfected with an artificial reporter construct and either ARNT or ARNT2 as a partner protein. CONCLUSIONS: Functional testing of the p.G715V variant revealed a significant reduction in SIM1-mediated transcriptional activity. We also generated the first ab initio hybrid protein model for full-length SIM1 to show the predicted spatial relationship between p.G715V and other previously described variants in this region and identified a putative mutation hotspot within the C-terminus. Significant clinical heterogeneity has been observed in patients with SIM1 variants, particularly with regards to the PWL phenotype. In the patient with ID, a second variant of uncertain significance in CHD2 was identified that may contribute to his ID and behavioral disturbances, emphasizing the role of additional genetic modifiers.

Genetic analysis in the bariatric clinic; impact of a PTEN gene mutation.

BACKGROUND: Pathogenic PTEN gene mutations are known to cause PTEN tumor hamartoma syndrome. Recent studies also suggest a role for PTEN mutations in the pathogenesis of obesity. No PTEN mutations have been reported among bariatric surgery patients and obesity treatment results are unknown. Since preventive screening for associated tumors is offered to patients with molecular proven PTEN hamartoma tumor syndrome, recognition of this condition in the bariatric surgery clinic is important. METHOD: We present a patient with morbid obesity who carries a known pathogenic PTEN mutation, identified at the bariatric surgery clinic using an obesity gene panel consisting of 52 obesity-associated genes. We analyzed the weight loss response during the first 3 years after Sleeve Gastrectomy. RESULTS: At 1, 2 and 3 years after surgery, the patient achieved a Total Body Weight Loss of 39.4%, 48.8% and 44.9%, respectively. This corresponds to the results of a control group of 18 female patients with normal genetic test results. CONCLUSION: Our patient illustrates the importance of recognizing this serious genetic condition for which preventive cancer screening options are available. The positive weight loss results after Sleeve Gastrectomy suggest that this could be a successful treatment option for obesity patients with PTEN mutations.

The pathogenesis of obesity.

Body fat mass increases when energy intake exceeds energy expenditure. In the long term, a positive energy balance will result in obesity. The worldwide prevalence of obesity has increased dramatically, posing a serious threat to human health. Therefore, insight in the pathogenesis of obesity is important to identify novel prevention and treatment strategies. This review describes the physiology of energy expenditure and energy intake in the context of body weight gain in humans. We focus on the components of energy expenditure and the regulation of energy intake. Finally, we describe rare monogenetic causes leading to an impairment in central regulation of food intake and obesity.

Gastric pouch emptying of solid food in patients with successful and unsuccessful weight loss after Roux-en-Y gastric bypass surgery.

BACKGROUND: After Roux-en-Y gastric bypass (RYGB), approximately 10% of patients have insufficient weight loss (excess body mass index loss<50%). Gastric pouch emptying may have a role in weight loss. OBJECTIVES: To compare pouch emptying of patients with poor weight loss and patients with successful weight loss after RYGB. SETTING: A research-intensive nonacademic hospital and center of expertise in bariatric surgery in the Netherlands METHODS: Female patients were included from among patients with the least (poor weight loss group [P-WL]) and the most weight loss (successful weight loss group [S-WL]) in our center 2 years after RYGB. Pouch emptying scintigraphy was performed after ingestion of a radiolabeled solid meal. Emptying curves, intestinal content (IC) at meal completion and after 15, 30, 45, and 60 minutes, half emptying time, and maximal pouch emptying rate were compared. RESULTS: Five individuals were included in P-WL and 5 in S-WL, on average 2.5 ± .3 years after RYGB. Total weight loss was 18 ± 4.1% in P-WL and 44 ± 5.7% in S-WL (P<.001). In P-WL, a fast initial pouch emptying and exponential emptying curve was observed, compared with a slower initial emptying and more linear curve in S-WL. Faster emptying in P-WL was also shown by a larger ICmeal (42 ± 18% versus 4.0 ± 3.3%,), IC15 (76 ± 15% versus 35 ± 22%), and IC30 (85 ± 12% versus 54 ± 25%), and a greater maximal pouch emptying rate (17 ± 4.7 versus 5.6 ± 3.4%/min) compared with S-WL (P<.05). A linear correlation was found between total weight loss and maximal pouch emptying rate (Pearson R = .82, P = .004). CONCLUSIONS: Pouch emptying for solid food was faster in patients with the least weight loss compared with patients with the most weight loss after RYGB. If pouch emptying is an important mechanism in weight loss, altering the pouch outlet may improve poor weight loss management.