Vascular and Interventional Radiology Review

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1 Vascular and Interventional Radiology Review Anton et al. Treating Obesity With Bariatric Left Gastric Artery Embolization Vascular and Interventional Radiology Review Kevin Anton 1 Tariq Rahman Ashok Bhanushali Aalpen A. Patel Anton K, Rahman T, Bhanushali A, Patel AA Keywords: bariatric embolization, ghrelin, gut hormone, left gastric artery embolization, obesity, weight loss DOI: /AJR Received January 4, 2015; accepted after revision May 6, Based on a presentation at the Image-Guided Intervention: 50th Anniversary meeting 2014, Portland, OR. 1 All authors: Department of Radiology, Geisinger Medical Center, 100 N Academy Ave, Danville, PA Address correspondence to K. Anton (kfanton@geisinger.edu). AJR 2016; 206: X/16/ American Roentgen Ray Society Bariatric Left Gastric Artery Embolization for the Treatment of Obesity: A Review of Gut Hormone Involvement in Energy Homeostasis OBJECTIVE. The global population is becoming more overweight and obese, leading to increases in associated morbidity and mortality rates. Advances in catheter-directed embolotherapy offer the potential for the interventional radiologist to make a contribution to weight loss. Left gastric artery embolization reduces the supply of blood to the gastric fundus and decreases serum levels of ghrelin. Early evidence suggests that this alteration in gut hormone balance leads to changes in energy homeostasis and weight reduction. The pathophysiologic findings and current evidence associated with the use of left gastric artery embolization are reviewed. CONCLUSION. The prevalence of obesity continues to increase at an alarming rate, and, thus far, advances in medical management have been relatively ineffective in slowing this trend. Lifestyle modifications such as diet and exercise are effective initially, but most patients regain the weight in the long term. Bariatric surgery is the most effective strategy for achieving longterm weight loss; however, as with all surgical procedures, it has potential complications. T he gastrointestinal tract in particular, the stomach is a key organ involved in energy homeostasis through the release of orexigenic, anorexigenic, and adipostatic hormones. Hormones such as ghrelin, leptin, obestatin, and insulin act through neural pathways in the hypothalamus to directly influence appetite, food intake, and energy expenditure. Each of these hormones is a target for potential drug therapy. Interventional radiologists, with their innovation and expertise in minimally invasive embolotherapy, have the potential to make a significant contribution to helping patients achieve weight loss. Left gastric artery embolization reduces the supply of blood to the gastric fundus and decreases serum levels of ghrelin. Some early evidence suggests that this alteration in gut hormone balance leads to changes in energy homeostasis and a reduction in weight. The rationale and pathophysiologic findings supporting the use of the technique and the most current research are reviewed. Background Obesity Long recognized as a global pandemic, the prevalence of obesity has nearly doubled since Overall, more than 10% of the global adult population is classified as obese, which is defined by a body mass index (BMI; weight in kilograms divided by the square of height in meters) greater than or equal to 30 [1]. In the United States, more than one third of the adult population (34.9%) is classified as obese [2]. Overweight (defined by a BMI 25) and obesity are major risk factors for global mortality. In the adult population, at least 2.8 million deaths are deemed to occur annually secondary to individuals being overweight or obese. Recent data suggest that obesity may be associated with nearly 20% of all deaths [3]. The World Health Organization estimated that, worldwide, 42 million children younger than 5 years of age were overweight or obese in 2013 [1]. This statistic will increase to 70 million children by 2025, if the current trend continues. In addition to a risk for obesity-related morbidity in childhood, these children also have an increased risk for obesity, premature death, and disability during adulthood. Obesity is a major risk factor for cardiovascular diseases (e.g., heart disease and stroke), diabetes, musculoskeletal disorders, and certain neoplasms. The risk of disease has been shown to increase with an increase in BMI. This produces significant health-related and economic burdens on the health care system. In 2008, the total cost of medical care associated with obesity was $147 billion [4]. For the obese patient, a 5 10% decrease in weight 202 AJR:206, January 2016

2 Treating Obesity With Bariatric Left Gastric Artery Embolization D Fig. 1 Anatomic manipulation of common bariatric surgery procedures. A E, Illustrations show Roux-en-Y gastric bypass (A), adjustable gastric banding (B), vertical sleeve gastrectomy (C), biliopancreatic diversion (D), and biliopancreatic diversion with duodenal switch (E). (Reprinted with permission from [54]) produces a significant benefit in delaying or preventing comorbid complications. Obesity is a multifactorial condition that is influenced by genetics, the environment, and other diseases, drugs, or psychologic factors. As with other multifactorial conditions, treatment of obesity requires that a multidisciplinary approach be tailored to the individual. A Medical Management: Lifestyle Changes and Pharmacotherapy Management of weight loss is a multidisciplinary effort between the patient, primary care physician, dietitian or nutritionist, physical trainer, and support groups. The major components of this treatment approach are caloric reduction and increased physical B E C activity and exercise. The initial goal is to achieve a 5 10% reduction in weight during the first 6 months of the treatment program [5]. Despite being associated with early benefits, lifestyle and dietary changes have proven ineffective as long-term treatment of most obese individuals. For patients who do not achieve a desirable weight loss by means of lifestyle changes alone, there are three approved weight loss medications: orlistat, lorcaserin, and phentermine-topiramate. Orlistat acts by reducing the amount of fat absorbed by the body. Lorcaserin acts on the serotonin receptors in the CNS to promote a feeling of fullness despite consumption of smaller portions of food. Phentermine-topiramate suppresses appetite and curbs the desire to eat. The percentage of patients who achieve clinically meaningful weight loss (at least 5% of their body weight) varies according to the medication used. A previous study found that 37 47% of patients taking lorcaserin, 35 73% of patients taking orlistat, and 67 70% of those taking the maximum dose of phenterminetopiramate had adequate weight loss [6]. Antiobesity medications are not without significant side effects. Potential side effects of lorcaserin include headache, upper respiratory tract infection, dizziness, fatigue, back pain, dry mouth, nausea, constipation, and mitral regurgitation [7 9]. Common side effects of phentermine-topiramate include dizziness, insomnia, constipation, dry mouth, paresthesia, and dysgeusia [10]. These ad- AJR:206, January

3 Anton et al. verse effects are dose dependent, with symptoms increasing at higher doses [11]. Phentermine-topiramate is contraindicated in pregnancy because it increases the risk of oral clefts and other craniofacial defects. Orlistat frequently causes diarrhea, abdominal pain, flatulence, bloating, and dyspepsia [12]. Vitamin supplementation is recommended for patients taking orlistat because orlistat can potentially interfere with fat-soluble vitamin absorption. Rare cases of severe liver and kidney injury have been reported in association with orlistat as well [13, 14]. Medical therapies are adjuncts to lifestyle alterations and require adherence for their successful implementation. A postmarketing analysis of weight loss medications found that 25% of patients continued to purchase the medication after 4 months of therapy and that less than 2% of patients completed 12 months of therapy [15]. Because of limited medical and pharmacological therapeutic options and their associated side effect profiles, these therapies achieve suboptimal outcomes, leaving bariatric surgery as the most effective approach for achieving long-term weight loss. Bariatric Surgery Numerous surgical interventions target weight loss in the bariatric population. The most frequently used interventions include Roux-en-Y gastric bypass, the gastric lap band procedure, sleeve gastrectomy, and biliopancreatic diversion (Fig. 1). Five years after surgical intervention, the mean percentage of weight loss has been reported as 20 25% for the gastric lap band procedure and 25 30% for gastric bypass [16 18]. When the risks and benefits of bariatric surgery are weighed, the metrics for success include not only the percentage of weight loss achieved but also any improvement in multiple obesity-related comorbid conditions, which include diabetes mellitus type 2, hypertension, hyperlipidemia, longterm cardiovascular events, and obstructive sleep apnea [18]. The potential benefits of gastric bypass must be weighed against the known complications. Bleeding, infection, postoperative development of deep venous thrombosis, internal leaks at the incision site, respiratory problems, and death can complicate the early postoperative period. Longer-term complications include malnutrition, vitamin and protein deficiencies, gastric dumping syndrome, anastomotic stricture, staple-line failure, internal hernia, adhesions, pouch dilatation, and failure to lose a sufficient amount of weight. Contraindications to surgical intervention include a high risk of death while undergoing the procedure, the presence of comorbid illnesses associated with shortened life expectancy that would not Fig. 2 Illustration of gut hormone balance in energy homeostasis. Ghrelin, obestatin, and leptin bind their respective receptors in arcuate nucleus of hypothalamus, which integrates their signals and communicates with satiety center. Variations in gut hormone levels affect food intake and energy expenditure, leading to changes in weight. (Drawing by Anton J and Anton K) 204 AJR:206, January 2016

4 Treating Obesity With Bariatric Left Gastric Artery Embolization Ghrelin GHSR NPY/AgRP Neuron NPY AgRP Acting through second order hypothalamic neurons, the natural downstream effect of α-msh is to: Reduce appetite and food intake Reduce weight gain By inhibiting the release of α-msh, ghrelin acts to: Increase appetite and food intake Increase weight gain be improved by weight reduction, patient inability to understand the nature of the intervention, and patient noncompliance with medical care. Although they are not technically a complication, additional cosmetic procedures, such as removal of excess skin after dramatic weight loss, are frequently performed after successful bariatric surgery. Despite the long list of associated complications, bariatric surgery remains the most viable option for achieving significant sustained weight loss. It does, however, leave room for significant improvement with the use of novel minimally invasive interventions. Arcuate Nucleus NPY AgRP Y1/Y5 MC3/4 Ghrelin also downregulates anorexigenic receptors for: Peptide YY Glucagon-like peptide 1 Cholecystokinin POMC/CART Neuron α-msh α-msh Fig. 3 Diagram of ghrelin signaling pathway in appetite and energy homeostasis. Ghrelin binds growth hormone secretagogue receptor (GHSR) in neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons in arcuate nucleus of hypothalamus. NPY and AgRP subsequently bind NPY subtype 1 and 5 (Y1/Y5) and melanocortin-3 and melanocortin-4 (MC3/4) receptors on proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) neurons, inhibiting release of α-melanocyte-stimulating hormone (α-msh). Natural downstream effect of α-msh release, acting through second-order neurons in other hypothalamic nuclei, is to reduce appetite and food intake and reduce weight gain. By inhibiting α-msh, ghrelin acts to increase appetite and food intake and increase weight gain. Pathophysiologic Reasoning for Using Left Gastric Artery Embolization for Weight Loss Gut Hormones Through the release of regulatory peptide hormones, the gastrointestinal tract plays an intricate role in appetite regulation and, specifically, meal initiation and termination [19]. The homeostatic process of body weight regulation through regulation of appetite and feeding and energy balance is maintained by long- and short-term neural and humoral signals [20] (Fig. 2). Containing neuronal populations with gut hormone receptors, the arcuate nucleus of the hypothalamus is the major site of hormonal signal input and integration [21]. Increasing evidence suggests that alterations in the circulating levels of gut hormones after bariatric surgery are, in part, responsible for the postprocedural weight loss [19, 21, 22]. These alterations include stimulation of glucagon-like peptide-1, peptide tyrosine-tyrosine (PYY), and oxyntomodulin secretion and a reduction in ghrelin secretion. Ghrelin First discovered in 1999, ghrelin is a 28-amino-acid acylated peptide primarily produced and secreted by endocrine cells lining the gastric fundus. Ghrelin is intricately involved in the regulation of glucose homeostasis and energy metabolism. Ghrelin-producing cells in the stomach and proximal duodenum produce more than 90% of ghrelin used by the body. Gastrectomy results in an 80% reduction in plasma levels of ghrelin [23]. The remaining ghrelin is produced and secreted in the proximal intestine, pancreas, pituitary gland, and colon [24]. Because they are highly concentrated in the stomach fundus, ghrelin-secreting cells and, therefore, expression of ghrelin decrease as one moves from the fundus to the antrum [25]. A ligand for the growth hormone secretagogue receptor, ghrelin is the only known orexigenic hormone that stimulates secretion of growth hormone, increases appetite and food intake, and produces weight gain [26]. The predominant form of circulating ghrelin in plasma is des-acyl ghrelin, which has to be acylated by the gastric O-acyl transferase enzyme to become biologically active. Ghrelin is transported across the bloodbrain barrier, where it localizes and binds with its receptor in the pituitary gland, hypothalamus, hippocampus, and ventral tegmental region [27]. Ghrelin binds to neurons in the ventral tegmental region that project through the mesolimbic dopamine pathway to the amygdala, hippocampus, prefrontal cortex, and nucleus accumbens. Within the arcuate nucleus, ghrelin binds to the growth hormone secretagogue receptor on neuropeptide Y and agouti-related peptide neurons, stimulating release of neuropeptide Y and agouti-related peptide [28]. Neuropeptide Y and agouti-related peptide subsequently bind neuropeptide Y subtype 1 and 5 receptors and melanocortin-3 and melanocortin-4 receptors on proopiomelanocortin and cocaine- and amphetamine-regulated transcript neurons, thereby inhibiting the release of α-melanocyte-stimulating hormone [29]. The natural downstream effect of release of α-melanocyte-stimulating hormone, acting through second-order neurons in other hypothalamic nuclei, is to reduce appetite and food intake and reduce weight gain. By inhibiting α-melanocyte-stimulating hormone, ghrelin acts to increase appetite and food intake and increase weight gain (Fig. 3). Stimulation of appetite and food intake is also related to modulation of the mesolimbic-dopamine pathway by ghrelin [30, 31]. In addition, ghrelin downregulates anorexigenic hormone receptors for PYY, glucagon-like peptide-1, and cholecystokinin [32 34]. Circulating levels of ghrelin are elevated during preprandial and fasting states and decrease rapidly after feeding in the postprandial period [35]. In humans and animals, ghrelin increases food intake, and prolonged food restriction causes an increase in circulating ghrelin levels, acting as a protective mechanism against starvation [26, 36]. Ghrelin reduces sensitivity to gastric distention by decreasing the mechanosensitivity of the gastric vagal afferents [37]. Leptin Synthesized and secreted predominantly by adipose tissue, leptin is an adipokine, a AJR:206, January

5 Anton et al. cytokine-like hormone, known to play an important role in long-term regulation of energy homeostasis. In addition, leptin is involved in glucose regulation through the regulation of pancreatic β-cell function, reproductive hormone regulation, and T-cell immunity [38]. Leptin signaling is mediated through the hypothalamus and induces weight loss through suppression of food intake and metabolism stimulation [39]. Of interest, obese patients may be leptin resistant, which contributes to their inability to adequately suppress food intake or increase metabolism. For patients who use diet and exercise for weight loss, the decrease in body fat as they progress through their program leads to decreased serum levels of leptin [40]. Lower serum levels of leptin make maintenance of weight loss more difficult. Obestatin Encoded by the ghrelin precursor gene, obestatin is an anorexigenic hormone secreted by gastric mucosa that produces effects that are the opposite of those produced by ghrelin. Initial evidence suggested that obestatin decreases food intake, inhibits gastric emptying, and reduces body weight [41]. However, a subsequent study was unable to show the same results, and the role of obestatin in energy homeostasis remains controversial [42]. Similar to leptin, obestatin plays a role in the regulation of pancreatic β cells by promoting survival and proliferation and preventing β-cell apoptosis [43]. Evidence-Based Rationale for Using Left Gastric Artery Embolization Left Gastric Artery The left gastric artery (LGA) is the smallest branch of the celiac trunk, coursing upward to the superior aspect of the lesser curvature of the stomach. Before turning downward and coursing along the lesser curvature, the LGA gives off esophageal branches that anastomose with esophageal branches from the thoracic aorta, a hepatic branch, and cardiac branches that supply the cardiac portion of the stomach. The LGA commonly divides into anterior and posterior branches before reaching the lesser curvature. Traveling along the lesser curvature, the LGA gives off branches that supply both surfaces of the stomach, providing supply to the gastric fundus. Finally, the LGA anastomoses with the right gastric artery along the lesser curvature. Most commonly, the LGA originates from the celiac trunk. Less common independent origins include the aorta, splenic artery, common hepatic artery, and superior mesenteric artery. The LGA may give off aberrant branches, including a left hepatic branch and replaced common hepatic branch (Fig. 4). The superior aspect of the greater curvature of the stomach is supplied by the short gastric arteries and left gastroepiploic artery. Fig. 4 Illustrations of left gastric artery (LGA) variant anatomy. LGA most commonly originates from celiac trunk. Multiple variations of its normal origin and branch vessels have been identified, some of which are detailed here. LHA = left hepatic artery, LGA = left gastric artery, RHA = right hepatic artery, CHA = common hepatic artery, SA = splenic artery, GDA = gastroduodenal artery, SMA = superior mesenteric artery. (Drawing by Anton K based on data and illustrations from Song et al. [55]) 206 AJR:206, January 2016

6 Treating Obesity With Bariatric Left Gastric Artery Embolization Inferiorly, the greater curvature is supplied by the right gastroepiploic artery. A diffuse network of vessels courses along the stomach surface, creating anastomoses between the lesser and greater curvatures. Left Gastric Artery Embolization In 1973, what is, to our knowledge, the first reported instance of LGA embolization (LGAE) performed with the use of an autogenous blood clot to treat a gastrointestinal hemorrhage from a gastric ulcer of the lesser curvature was performed [44]. Since that time, advances in catheter-based embolotherapy have provided opportunities for safe targeting of select arteries while limiting nonselective effects [45, 46] (Fig. 5). Animal Trials In 2007, what is, to our knowledge, the first prospective study to show the ability of catheter-directed gastric artery chemical embolization to modulate systemic plasma levels of ghrelin in a porcine model was published [47]. A total of eight swine (two swine assigned to a control group, four swine receiving low-dose morrhuate sodium, and two receiving high-dose morrhuate sodium) underwent sclerotherapy of the LGA with the use of morrhuate sodium. The study showed a reduction in systemic levels of ghrelin without significant change in weight. Microulcers at the gastroesophageal junction were also noted in the treated animals. However, there were numerous study limitations, including the use of a toxic sclerosant (morrhuate sodium), a small sample size, differing sclerosant dosages, nontarget embolization techniques, and short-term evaluation. A follow-up study [48] confirmed that use of the gastric artery chemical embolization technique in swine decreased systemic levels of ghrelin over the 4-week study, with maximum suppression occurring at weeks 2 and 3. Ghrelin levels started to reverse at week 4. Rather than evaluate weight loss in an adult swine population, the investigators evaluated young swine, and they evaluated the natural weight gain in these young swine after gastric artery chemical embolization or a sham procedure was performed. A significant reduction in weight gain in the treated group (7.8% at week 4), compared with the control group (15.1% at week 4), was noted (p < 0.04). Advancing the work performed by Arepally et al., a prospective porcine model evaluating the effects of bariatric embolization on systemic levels of ghrelin and weight gain over 8 B C Fig. 5 Two patients who underwent left gastric artery (LGA) embolization. (Presented in poster format at Image-Guided Intervention: 50th Anniversary meeting in Portland, OR, July 23 24, 2014) A, 61-year-old male patient with acute upper gastrointestinal bleeding. 3D reconstructed CT angiography image shows normal origin of LGA (arrow) from celiac trunk. B and C, 52-year-old female patient with acute upper gastrointestinal bleeding. Arteriographic images show LGA before (B) and after (C) embolization. weeks was conducted using microspheres as the embolic agent [49]. With the use of 40-μm calibrated Embozene microspheres (CeloNova), a 55% reduction in serum levels of ghrelin was seen. In addition, the experimental group had less weight gain during the 8 weeks after the procedure, compared with the control group that underwent a sham procedure (3.6 vs 9.4 kg, respectively; p = 0.025). Paxton et al. [50] published a histopathologic evaluation of the gastric mucosa in swine that underwent embolization versus swine that received the sham treatment previously described. No mucosal ulcerations in the gastric fundus were identified; however, healed or healing ulcers were seen in the gastric body of three treated animals (50% of the experimental group). None of the ulcers had perforated or showed necrotic changes. An evaluation of the posttreatment cell volume producing ghrelin found statistically significant lower levels in treated animals, compared with control animals. Of interest, at 8 weeks after treatment, there was no upregulation of ghrelin by the duodenum. In a novel canine model, Bawudun et al. [51] showed decreased plasma levels of ghrelin, body weight, and subcutaneous fat in dogs that underwent LGAE, compared with control dogs that received sham treatment. The LGA was embolized with a combination of bleomycin and ethiodized oil (Lipiodol, Guerbet) A AJR:206, January

7 Anton et al. TABLE 1: Published Animal Studies Evaluating the Role of Left Gastric Artery Embolization (LGAE) in Weight Loss Authors [Reference] Year Study Design No. of Subjects Change in Ghrelin Levels Change in Weight Notes Arepally et al. [47] 2007 Prospective study, porcine model Arepally et al. [48] 2008 Prospective study, porcine model Bawudun et al. [51] 2012 Prospective study, canine model Paxton et al. [49] 2013 Prospective study, porcine model emulsion or polyvinyl alcohol (500- to 700-μm particles). Control animals had saline injected after they underwent selective catheterization of the LGA. The peak reduction in plasma levels of ghrelin occurred at week 3 in both LGAE groups. Ghrelin levels then showed a compensatory increase toward baseline levels until week 6 or 7, at which time they again sharply decreased. In both the sclerosant and polyvinyl alcohol LGAE groups, there was a significant reduction in body weight, with peak reduction occurring at week 2 or 3. Comparison of the animal studies is shown in (Table 1). Total of 8 swine: 2 swine in control group, low-dose GACE group: 4 in low-dose GACE group, and 2 in high-dose GACE group a Total of 10 swine: 5 in control group and 5 in GACE group Total of 15 canines: 5 in control group, 5 in group receiving bleomycin and ethiodized oil plus LGAE, and 5 in group receiving PVA particles plus LGAE Total of 12 swine: 6 in control group and 6 in GACE group Control group: no significant change; low-dose GACE group: 245% ± 34% increase; high-dose GACE group: 104% ± 23.4% increase Control group: 2.6% increase at 3 weeks and 18.2% increase at 4 weeks; GACE group, 42.5% decrease at 3 weeks and 12.9% decrease at 4 weeks Control group, 13.6% increase; group receiving bleomycin and ethiodized oil plus LGAE, 15.8% decrease; group receiving PVA particles plus LGAE, 30.2% decrease Mean (± SD) value: for control group, increase of ± 129 pg/dl; for GACE group, decrease of ± pg/dl Human Trials A retrospective review that compared 19 patients who underwent LGAE with 28 patients who underwent embolization of a separate artery for gastrointestinal bleeding found a statistically significant reduction in the body weight of patients in the LGAE group (7.3%) versus the control group (2%), in the first 3 months after the procedure was performed [52]. No statistically significant difference was seen at later points in time, which were not standardized (13.6 months in the experimental group vs 4 months in the control group). In addition, both groups included patients with documented malignancies. At the American College of Cardiology annual meeting in 2013, Kipshidze et al. [53] presented findings from what, to our knowledge, is the first prospective human study of five patients who underwent LGAE specifically for the management of obesity. In that study, patients lost an average of 45 pounds by 6 months after the procedure. However, ghrelin levels, which had initially decreased (to 36% below the baseline level at 3 months after LGAE), were increasing at the time of the 6-month follow-up (to 18% below the baseline level). Comparison of the studies involving humans is shown in (Table 2). Mean (± SD) value at 4 weeks: control group, 8.6% ± 0.9% increase; GACE group (low dose and high dose): 1.4% ± 10.9% increase; no statistically significant difference Mean (± SD) value at 4 weeks: control group, 15.1% ± 6% increase; GACE group, 7.8% ± 5.5% increase For control group, percentage increase from baseline weight; for both LGAE groups, percentage decrease from baseline weight (peak percentage reduction occurred at week 2 or 3) Mean (± SD) value over 8-week follow-up: for control group, increase of 9.4 ± 2.8 kg; for GACE group, increase of 3.6 ± 3.8 kg Dose-escalating trial (for each administered dose, n = 1), created widely varied results For embolization, sodium morrhuate (50 mg/ml, 5%) was delivered through the catheter at a dose of 125 g Amount of subcutaneous fat was also decreased in the LGAE groups vs the control group Control animals underwent sham procedure with 5 ml of saline; GACE was performed with 4 6 ml of diluted 40-μm calibrated microspheres in saline Note GACE = gastric artery chemical embolization; ethiodized oil = Lipiodol (Guerbet); PVA = polyvinyl alcohol. a The four swine in the low-dose GACE group underwent sclerotherapy of the LGA with a low dose of morrhuate sodium (37.5, 50, 56.25, and 62.5 mg), whereas the two swine in the high-dose GACE group underwent sclerotherapy of the LGA with high dose of morrhuate sodium (125 and 2000 mg). Future Challenges For more than 40 years, LGAE has been performed alone or in combination with embolization of additional arteries in the setting of gastrointestinal bleeding. However, to our knowledge, no trials specifically evaluating the safety of embolizing the blood supply to the gastric fundus have been conducted. The most significant complication noted in animal studies is postprocedural gastric ulceration. Dedicated phase 1 trials that address the safety of gastric fundal embolization in humans need to be carefully constructed, to clearly define the gastric ulcer rate. Some of the early ongoing trials include the Gastric Artery Embolization Trial for Lessening Appetite Nonsurgically (GETLEAN) and the Bariatric Embolization of Arteries for the Treatment of Obesity (BEAT Obesity). These trials will begin to define the role of transarterial embolization in weight loss, because significant questions remain. One possibility is that LGAE provides temporary reduction in ghrelin levels and weight loss and that, through a combination of gut hormone rebalancing and revascularization, these levels return to baseline over time. In 208 AJR:206, January 2016

8 Treating Obesity With Bariatric Left Gastric Artery Embolization TABLE 2: Published Human Studies Evaluating the Role of Left Gastric Artery Embolization (LGAE) in Weight Loss Author [Reference] Year Study Design No. of Subjects Embolization Materials Used Change in Weight Notes Gunn and Oklu [52] 2014 Retrospective Total of 28 subjects in the control group (15 male patients, 13 female patients; average age 58.7 years; average BMI, 29.2); total of 19 subjects in the LGAE group (12 male patients, 7 female patients; average age, 64.6 years; average BMI, 30.3) Kipshidze et al. [53] 2013 Prospective, single-arm human model the morbidly obese patient, this may still provide some clinical benefit, perhaps as an initial reduction in weight that can then be combined with dietary and lifestyle changes. In addition, as seen with bariatric surgery, LGAE may provide an improvement in diabetes with a reduction in hemoglobin A1c levels, representing another issue that requires investigation. Furthermore, LGAE may play a complementary or adjunctive role, in combination with bariatric surgery. It is clear that LGAE decreases serum levels of ghrelin by reducing secretory cells in the gastric fundus; however, to our knowledge, no study has yet evaluated how these alterations in ghrelin affect other gut hormones, including leptin and obestatin. In the long term, it may prove beneficial to treat patients undergoing LGAE with a supplementary therapy that targets one or more gut hormones involved in humoral rebalancing, to achieve energy homeostasis. As the bariatric embolization technique evolves, additional studies evaluating the access site, embolization material, particle size, degree of embolization, benefit of peri- and postprocedural medications (such as proton pump inhibitors or sucralfate [Carafate, Forest Laboratories]), and follow-up of long-term occlusion (recanalization, collateral vascularization, or both) will become important for procedural standardization. Although the early results of LGAE have been promising, there are many more questions that need to be addressed before this Five patients who received LGAE For the control group: coils (n = 23), gel foam (n = 3), and PVA particles (n = 2); for the LGAE group, coils (n = 9), gel foam (n = 5), and PVA particles (n = 5) a Embolic beads ( μm microspheres, Bead Block, Terumo) Note BMI = body mass index (weight in kilograms divided by the square of height in meters), PVA = polyvinyl alcohol. a PVA particle sizes were μm, μm, and μm, as chosen on the basis of operator preference. technique can be implemented on a nonresearch basis. A better understanding of the long-term effects on patients and the pathophysiologic profile of the procedure will better elucidate the role that LGAE will play in the management of obesity. Conclusion Early data suggest that targeted embolization of the arterial supply to the gastric fundus may provide a safe effective approach to weight loss in the obese patient. The major complication noted in animal studies is postembolization gastric ulcer formation. No ulcers were found in the first human cohort study; however, larger phase 1 trials, followed by phase 2 and 3 trials with long-term follow-up, will be necessary to better elucidate the role of LGAE gastric artery embolization in the management of obese patients. References 1. World Health Organization. Obesity and overweight: fact sheet no World Health Organization website. fs311/en/. Published Updated January Accessed September 21, Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, JAMA 2014; 311: Masters RK, Reither EN, Powers DA, Yang YC, Burger AE, Link BG. 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