Bariatric embolization for the treatment of obesity

Abstract

Introduction

Bariatric embolization, also known as left gastric artery embolization, is a recently introduced endovascular image-guided procedure aimed at treating obesity.1 This procedure entails percutaneous transarterial particle embolization of the gastric fundus arterial supply, which is the site of the highest concentration of ghrelin-secreting cells in the body. By doing so, it is hypothesized that the intentionally induced ischemia in the gastric fundus will result in depressed serum ghrelin levels, which may decrease hunger, decrease food intake, and thereby induce weight loss. The goal of this review article is to discuss the background, rationale, and existing data on this new and burgeoning topic.

Obesity

In 1997, the World Health Organization designated obesity as a global epidemic, marking the first time in history that a noninfectious malady has been labeled as an epidemic.2 In 2008, >1.4 billion adults were overweight, with a body mass index (BMI) of ≥25. Five hundred million were obese, with a BMI of ≥ 30.3 Thus, 11% of the world’s population was classified as obese. The rate of obesity is growing, with an incidence that has nearly doubled since 1980.

Obesity is ranked as the fifth leading risk for mortality globally.3 Obesity has been strongly linked to numerous comorbidities, including type II diabetes, hyperlipidemia, hypertension, obstructive sleep apnea, heart disease, stroke, asthma, cancer, and depression.4 The link is actually strong – for example, the risk of diabetes increases 18-fold in obese patients. The increase in relative risk of coronary artery disease in middle-aged men is 72% higher, even with only mild obesity. In aggregate, these obesity-related comorbidities have been reported to be responsible for >2.5 million deaths per year worldwide. Not surprisingly, life expectancy is profoundly affected by obesity. For example, a 25-year-old morbidly obese man can expect a 22% reduction in lifespan.5 In fact, an expert panel convened by the National Institutes for Health stated that for the first time in history, the steadily improving worldwide life expectancy could level off or even decline within the first half of this century, specifically as the result of the increasing prevalence of obesity.6

The fundamental cause of obesity is an energy imbalance, with more calories being consumed than expended. The global rise in obesity can be attributed at least in part to the increased intake of high-calorie and high-fat foods and a decrease in physical activity related to the increasingly sedentary lifestyles resulting from modernization and automation. However, numerous additional etiologies and pathologies are also known to be responsible for obesity.

Regulation of hunger

The hormonal regulation of hunger is complex, and is primarily governed by hunger-inhibiting hormones.7 Mechanical and chemical factors associated with meals stimulate enteroendocrine cells, resulting in signals transmitted neutrally through vagal nerves and/or circulating hormones. The end result is modulation of hunger in the central nervous system. Short-term hunger modulation in response to meals is largely due to cholecystokinin. Longer-term regulation of energy balance and weight is controlled largely by the effects of insulin and leptin. Although >40 hormones have been shown to inhibit appetite, only ghrelin has been shown to stimulate appetite.7

Ghrelin

Ghrelin is a peptide hormone that is secreted primarily from the gastrointestinal tract, with the highest concentration in the fundus of the stomach, with progressively decreasing concentrations in the small and large intestines. Ghrelin was first identified and reported in the literature in 1999 as an endogenous ligand for the growth hormone secretagogue receptor.8 Additionally, ghrelin directly stimulates appetite and induces positive energy balance, resulting in body weight gain. Ghrelin is also expressed in the pancreatic islets, hypothalamus, and pituitary gland. In addition to stimulating appetite, ghrelin has also been shown to increase circulating growth hormone, adrenocorticotropic hormone, cortisol, prolactin, and glucose.9 Given the relatively recent discovery of ghrelin and incomplete understanding of its functional role, it likely has additional effects on other hormones and functions. Due to the unique nature of this hormone and its effect on appetite, multiple approaches to modulate ghrelin production have been attempted. Although various reports of ghrelin suppression have been described, none to date have been clinically practical, including intraventricular and large intraperitoneal delivery of ghrelin antagonists in rats, as well as a ghrelin vaccine.10–13

Gastric distribution

The detailed distribution of ghrelin-expressing cells has been reported in two separate studies.14,15 Although Kim et al14 analyzed gastric specimens from patients with gastric cancer undergoing total gastrectomy, Goitein et al15 analyzed resected gastric specimens from patients undergoing sleeve gastrectomy, which entails vertical resection of most of the stomach volume, including the entire fundus, most of the gastric body, and part of the antrum. In both studies, polymerase chain reaction analysis of ghrelin mRNA and immunostaining for ghrelin-expressing cells were performed throughout the resected specimen. In both studies, ghrelin mRNA and ghrelin-expressing cells were identified throughout the entire stomach; however, the concentrations of ghrelin mRNA and ghrelin-expressing cells were statistically highest in the gastric fundus, and lowest in the gastric antrum. Kim et al14 reported a ghrelin/actin mRNA ratio of 0.78 in the fundus, 0.20 in the body, and 0.07 in the antrum, reflecting a 10-times higher ghrelin concentration level in the fundus compared to the antrum. Goitein et al15 similarly reported a ghrelin/ribosomal mRNA ratio of 0.043, 0.026 and 0.015, respectively, which is an approximately three-times higher level in the fundus than antrum.

Treatment options for obesity

Diet and exercise regimens, while effective, have been shown to be difficult to maintain in the long term.16 Plasma ghrelin levels have been shown to rise sharply shortly prior to meals, which correlates with hunger that occurs just prior to consuming meals.17 Conversely, ghrelin levels fall shortly after each meal, which correlates to the satiation of hunger after consuming food. Diet regimens to induce weight loss have been shown to be difficult to sustain, due to the increase in hunger.16 Thus, it may not be surprising that dieting induces a 24% increase in the 24-hour ghrelin profile (P = 0.006).17 This elevated ghrelin secretion may therefore be a reason why dieting is so difficult to sustain in the long term.

Pharmacological modulation of hunger would be perhaps the ultimate means of controlling appetite and weight. Despite great efforts in this area, current pharmacotherapeutics can achieve only modest levels of weight loss with a range of 2.0–6.5 kg of sustained weight loss.17 Although bariatric surgery has proven to result in substantial degrees of sustained weight loss, the surgical risk in this patient population is significant. Alterations in ghrelin levels also occur with bariatric surgery. After gastric banding, there has been shown to be a 27% increase in serum ghrelin levels, which may be undesirable if patients experience increased hunger.18 The results with roux-en-Y gastric bypass are somewhat controversial.

Although some studies have demonstrated a decrease in serum ghrelin, others have shown ghrelin levels to be unchanged.19–21 However, with sleeve gastrectomy, the levels of serum ghrelin have been shown in multiple studies to be markedly decreased by ~60%.20,21 In fact, ghrelin depression has been shown to be significantly depressed even as far as 5 years post-surgery.22 Considering that the majority of the gastric fundus is removed during sleeve gastrectomy, there would certainly be a loss of a large proportion of ghrelin-secreting cells. Many have postulated this as one of the primary reasons why sleeve gastrectomy is the most effective of the bariatric surgeries, and conversely, a reason why surgeries that have no gastric tissue resection, such as gastric banding, have poor efficacy.

Gastric artery chemical embolization

The initial discovery that introduced the concept of destruction of ghrelin-producing cells by minimally invasive catheter-directed techniques was reported by Arepally et al23 in 2007. In this pilot study, the authors demonstrated that infusion of sodium morrhuate, a varicose vein sclerosant, into the left gastric artery of swine resulted in elevated serum ghrelin levels with low doses, but depressed serum ghrelin levels at moderate doses. Notably, at high doses, death resulted secondary to gastric necrosis and perforation. Arepally went on to perform gastric artery chemical embolization (GACE) in a larger number of swine using the higher doses, with a control arm to assess for differences in ghrelin level and weight over a 4-week period.24 Again, the serum ghrelin levels in treated animals were shown to be significantly depressed compared to controls. In these growing swine, the mean weight was statistically lower at 3 weeks and 4 weeks compared to untreated controls. However, the mean serum ghrelin levels demonstrated a 51% increase at 4 weeks, suggesting that the effect may be transient.

Bariatric embolization in a porcine model

Bariatric embolization in a canine model

Contemporary to our study, Bawudun et al29 conducted a similarly designed study in a canine model. However, in addition to a particle embolization treatment group, a chemical embolization group (bleomycin plus lipiodol) was also used. Bleomycin is a chemotherapeutic agent that causes strand breaks in DNA and is also used as a chemical sclerosant for pleurodesis. The particle embolization group was treated with 500–700 μm polyvinyl alcohol (PVA) particles.

Over an 8-week period, the authors reported that plasma ghrelin levels and body weight were significantly decreased in both treatment groups compared to controls. Several additional important parameters were analyzed. The abdominal body fat was quantified using computed tomography performed pre-procedurally and at 8 weeks. Both visceral and subcutaneous fat were quantified. The subcutaneous fat was significantly decreased in both treatment groups, whereas visceral fat was not. Gastric peristalsis was assessed at 8 weeks with a barium study of the stomach, with the conclusion that the gastric peristalsis appeared normal. Histopathological analysis demonstrated no difference in parietal cell structures comparing treated animals to controls. No gastric ulcers were identified.

Two important differences in the model are worth highlighting, compared to the swine model studies. First, the animals were on average 2 years old, and thus beyond the active growth stage. Thus, this model would more closely approximate the use of bariatric embolization in human adults, and the significant decrease in the amount of subcutaneous fat over 8 weeks is important and highly promising. The second and perhaps more important finding is that no gastric ulcers were detected in this study. At least two technical factors may be responsible for this finding. In this study, the authors used larger particles for embolization, measuring 500–700 μm, whereas in the swine study, 40-μm particles were used. The other factor may be that only one artery, that is, the left gastric artery, was treated in the canine study, whereas all four arteries supplying the gastric fundus were treated in the swine study. These factors may be useful for determining the optimal technique by which to perform bariatric embolization safely and efficaciously.

Human trials

In a retrospective fashion, Oklu et al30 presented the results of a single-institution cohort study of 15 patients who underwent transcatheter embolization of the left gastric artery for the indication of gastric hemorrhage, in comparison with a cohort of 18 age-matched patients who underwent embolization of any non-left gastric artery for treatment of upper gastrointestinal hemorrhage. Analysis of resultant weights over the subsequent 3 months revealed a 7.9% mean decrease in body weight for patients undergoing left gastric artery embolization compared to a mean 1.2% decrease in body weight for those undergoing embolization of a different upper gastrointestinal artery (P = 0.001). Embolic agents included particulate agents, coils, or a combination.

Kipshidze et al31 reported the results of a first-in-human prospective study of left gastric artery embolization in five patients. In this series, patients underwent embolization of the left gastric artery with 300–500-μm microspheres. Three patients reported transient abdominal pain. Endoscopy performed in all patients at 1 week post-procedure revealed no significant abnormalities. The mean weight, body mass index, and ghrelin levels were decreased at 1 month, 3 months and 6 months post-procedure (Table 1).

Future directions

In conclusion, the concept of an endovascular treatment for obesity has demonstrated promising preliminary data in animals and humans. However, the number and power of these studies is still somewhat marginal, and thus additional preclinical studies are needed to elucidate the mechanisms of this procedure. However, given the extremely complex physiology and mechanisms affecting appetite, weight gain, and weight loss, ultimately human trials are crucial prior to routine clinical use. To that end, multiple human trials have been initiated in multiple countries. Although primary efforts in these clinical trials were aimed at demonstrating safety, proving efficacy in terms of ghrelin levels, hunger and weight loss were also important components of these clinical trials. Perhaps more importantly, the duration of any effects will be a crucial factor in determining the future potential of this promising therapy. Once safety and basic efficacy are shown in further preliminary clinical trials, a full randomized clinical trial comparing bariatric embolization to various other treatments of obesity is destined to take place. If proven effective and safe, this endovascular method for treatment of obesity has great promise for playing a pivotal role in the treatment of one of the biggest epidemic health issues worldwide.

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