Abstract
Acquired hypothalamic obesity (HO) is a rare type of obesity caused by acquired disease-related and/or treatment-related damage to the hypothalamus, most commonly craniopharyngiomas. Effective management of HO is critical due to its significant impact on quality of life and resistance to conventional treatments. This systematic review and meta-analysis aims to evaluate the 12-month, 24-month and 60-month outcomes of bariatric surgery for HO caused by CPs compared with patients with common obesity (CO). Relevant studies were identified in MEDLINE and EMBASE databases until May 2024. A total of four matched case-control studies were included. The results indicated that bariatric surgery significantly reduced weight in patients with HO (22.98 ± 14.22/21.47 ± 9.61/19.07 ± 16.12% total weight loss, 12/24/60 months after surgery), but the effect was significantly less than that in CO controls (−6.17/−6.41/−7.72% total weight loss 12/24/60 months after surgery). Bariatric surgery can significantly reduce body weight in craniopharyngiomas-related HO, but the effect is less than that in matched patients with common obesity. Further studies are necessary to determine the best surgical or multidisciplinary approach to the treatment of acquired HO.
Introduction
Hypothalamic obesity (HO) is a rare type of morbid obesity caused by disease-related and/or treatment-related damage to the hypothalamus, including acquired factors such as craniopharyngiomas (CPs), germ cell tumors and Langerhans cell histiocytosis, and genetic neurodevelopmental factors such as Alström syndrome and Prader–Wili syndrome disrupting central leptin-melanocortin pathway (1, 2). CP and its radical treatment, including surgical resection and radiotherapy, are the most common causes of acquired HO (3). Even with optimal endocrine management, HO remains a frequent complication. In a consecutive series of 120 CP cases, 30% of the patients developed postoperative HO, with an 18% weight increase on average (4).
The hypothalamus is the command center of satiety, growth, body temperature and many other homeostasis functions. Hypothalamic syndrome (2) refers to the series of clinical manifestations of hypothalamic malfunction including memory deficits, temperature dysregulation, neuropsychological dysfunction, eating disorders, imbalance of circadian rhythms, and most evidently, HO. Many of the accompanied pathological changes are associated with the development of HO (5). Damages to the ventromedial nucleus of the hypothalamus and the arcuate nucleus lead to an imbalance of satiety hormones such as polypeptide-Y and glucagon-like peptide-1 and consequently hyperphagia (6). Decreased sympathetic activity reduces overall metabolic rate, prompting adipose storage (7).
The multifaceted etiologic feature of HO makes it resistant to conventional treatments of obesity. Pharmacotherapies, including a combination of diazoxide and metformin (8), sibutramine (9) and exenatide (10), have been tested for efficacy in the treatment of HO, but results are unsatisfactory. Semaglutide recently achieved an average total weight loss percentage (%TWL) of 17% in a case series of four females (11). One alternative is bariatric surgery, an essential treatment for severe obesity that outperforms lifestyle interventions and medications (12) by reducing the size of the stomach, altering digestive processes and modifying gut hormones to increase satiety and insulin sensitivity (13). Preliminary clinical studies have shed light on the efficacy of bariatric surgeries on HO caused by CPs, but a meta-analysis of matched case-controlled studies remains absent.
The present paper conducts a comprehensive systematic review and meta-analysis of the existing literature on the efficacy of bariatric surgery in patients with HO versus matched CO counterparts to provide sound evidence for the development of treatment strategies for CP-related HO.
Materials and methods
Data sources and searches
We performed a systematic review of available literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 framework. A thorough literature search was conducted across the PubMed and Embase databases from inception to 30 March 2024. We employed the PICO (population, intervention, comparison, outcome) search strategy (Supplementary Table 1, see section on supplementary materials given at the end of this article): population consists of CP-related HO; Intervention under study was any type of bariatric surgery; individuals with common obesity (CO) characterize comparison group; outcomes were evaluated as %TWL. Additionally, the reference lists of screened articles were reviewed to ensure comprehensive coverage. Two individuals (He and Xu) conducted the literature search separately to ensure complete coverage.
Study selections
Studies were eligible if they included a) patients with CP-related HO, b) who received bariatric surgery, c) that were matched and compared with patients with CO on bariatric procedure, gender, age and pre-operative BMI, d) and provided quantitative data of weight at 12 months or more after bariatric surgery. Studies were excluded if they a) were reviews, animal studies, or unmatched, b) did not provide sufficient data for weight loss analysis. Two individuals conducted study selections separately to ensure accuracy.
Data extraction
The following data were extracted: a) study characteristics (first authors, publication year, type of bariatric surgery, number of patients, mean age, BMI, study design, study cohort and recruitment period, inclusion and exclusion criteria, primary and secondary outcome, and follow-up period); b) TWL in both percentage and absolute quantity at all follow-ups.
Quality assessment
Bias risk in each study was evaluated by two independent reviewers (He and Xu) utilizing the Newcastle-Ottawa Quality Assessment Scale for Case-Control Studies (https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp). The consistency of the quality assessment between the two evaluators was verified, and differences were settled through consensus.
Notably, Weismann et al. (14) did not match the pre-operative BMI of the control group and HO group. Sensitivity analysis indicated that inclusion of this study substantially raised heterogeneity of the meta-analysis at both 1-year and 2-year follow-up time (I2 = 96%/40% if included, I 2 = 0%/0% if excluded, 12 months post-operative/24 12 months post-operative). To ensure statistic consistency, this study was excluded.
The evidence quality for each outcome parameter was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework (15). Two reviewers (He and Xu) assessed all study outcomes, and disagreements were settled through consensus.
Statistical analyses
We analyzed the reported percentage change in weight from baseline to 12 months, 24 months and 60 months post-surgery across different types of bariatric procedures. Weight losses were shown as means ± s.d . We aggregated the data to evaluate the impact of bariatric surgeries on HO and CO, using the inverse variance method in the random effects model. Subgroup analyses were conducted on sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). The proportion of variability in studies due to heterogeneity rather than chance was calculated using the I2 statistic. The analysis was conducted using RevMan 5.4. If a mean value involves multiple studies, it is calculated using a weighted average based on sample sizes. Data from two studies(van Santen and Winjin) (16, 17) are presented in confidence intervals, which we convert into standard error after carefully reviewing their baseline data and normal distribution.
Results
Search results
The search strategy (Fig. 1) yielded a total of 27 articles, of which 23 articles were excluded: 9 due to duplication, 4 due to ineligible article type, 4 due to content irrelevancy, 4 due to lack of comparison group, 1 due to unmatched comparison, 2 due to incomplete follow-up data. Reasons for exclusion are detailed in Supplementary Table 2. The articles identified were mainly observational cohorts and case-control studies. No randomized controlled trials were found.
During the qualitative assessment, 3 articles were rated as ‘good,’ and 1 was rated ‘poor’ (Supplementary Table 3). The evidence quality for all outcome measures was rated as ‘very low’ quality, as they were observational studies with small sample sizes (Supplementary Table 4). Heterogeneity among effect sizes was low except for the RYGB subgroup.
Key characteristics of included studies
The key characteristics of all included studies are shown in Table 1. The 4 studies enrolled patients from 7 different countries and included a total of 52 patients with CP-related HO, who were matched with 5.77 individuals CO per HO individual. For the HO group, the mean age at CP treatment was 20.61 years and the mean age at bariatric surgery was 32.27 years. The mean BMI before bariatric surgery was 44.35 kg/m2. The average follow-up time for patients with HO after bariatric surgery was 51.74 months. As for the type of bariatric surgery, in the HO group, 34.56% of the patients underwent SG, and 65.44% underwent RYGB. In the control group, 31.71% of patients underwent SG and 68.29% underwent RYGB. A summary of matching strategies and loss of follow-up can be found in the supplementary file.
Key characteristics of included studies: All data are average unless otherwise noted.
| Study | Hypothalamus obesity group | Common obesity group | Major inclusion criteria | Primary outcome | Secondary outcome | Follow-up period (years) | ||
|---|---|---|---|---|---|---|---|---|
| Surgery type/ BMI/weight pre-surgery(kg/m2)/(kg) | N/Sex/Age | Surgery type/BMI/weight pre-surgery(kg/m2)/(kg) | N/sex/age | |||||
| Faucher et al. 2022 (35) | SG (39%), RYGB (61%), 44.2/125.3 | 23, 8M/15F, 35 years | SG (39%), RYGB (61%), 46.7/120.6 | 46, Sex uncertain, 34.5 years | Age ≥ 18 years, diagnosis of proven craniopharyngioma and underwent bariatric surgery, ≥2 years of postoperative follow-up data. | Total weight loss (%) | T2D remission rate, adverse events | 5 |
| Garrez et al., 2020 (18) | SG (40%), RYGB (60%), 41.3/123.9 | 5, 1M/4F, 38 years | SG (40%), RYGB (60%), 41.1/117.2 | 10, 2M/8F, 43 years | Hypopituitarism and bariatric surgery as treatment for uncontrolled weight gain secondary to treatment of a CP | Total weight loss (%), excess weight loss (%) | NA | 2 |
| van Santen et al., 2021 (17) | SG (25%), RYGB (75%), 46.0/122.7 | 16, 4M/12F, 26 years | SG (25%), RYGB (75%), 45.1/118.5 | 155, 36M/119F, 31 years | History of craniopharyngioma and bariatric surgery to treat hypothalamic obesity | Total weight loss (%) | Cardiometabolic Features, complications after bariatric surgery | 5.2 |
| Wijnen et al., 2017 (16) | SG (37.5%), RYGB (62.5%), 43.3/122.5 | 8, 1M/7F, 33.4 years | SG (40%), RYGB (60%), 40.3/111.7 | 75, 9M/66F, 34.2 years | Patients with craniopharyngioma who underwent bariatric surgery | Total weight loss (%) | NA | 2 |
*Age is presented as median.
F, female; M, male.
Total weight loss at 12 months after bariatric surgery
All four studies examined %TWL at 12 months after bariatric surgery, which accumulated 52 patients with HO and 256 CO controls. The mean weight reduction ranged from 17.8% to 25.9% in patients with HO and 25% to 31.4% in patients with HO. Among the patients with HO, 34 received RYGB, and 18 received SG. The mean and s.d. of %TWL for HO at 12 months post-surgery was 22.98% ± 14.22%. The overall effect showed that patients with HO lose significantly less weight than patients with HO (mean difference: 6.17%, 95% Cl : −8.74%–−3.60%, P < 0.001, I 2 = 0%), as shown in Fig. 2.
Forest plot of %TWL of patients with HO 12 months after bariatric surgery. (A) It represents the combined analysis. (B) It represents the subgroup analysis for RYGB. (C) It represents the subgroup analysis for SG.
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0493
Subgroup analysis showed a significant reduction in weight loss between HO and CO patients for RYGB (mean difference: −7.92, 95% Cl: −14.04–−1.80, P = 0.01, I2 = 84%) and a non-significant difference for SG (mean difference: −3.87, 95% Cl: −7.29–−0.45, P = 0.03, I2 = 0%). Garrez et al. (18) did not disclose subgroup data and their study was left out of the analysis.
Total weight loss at 24 months after bariatric surgery
Three studies examined %TWL at 24 months after bariatric surgery, which accumulated 25 patients with HO and 188 CO controls. The mean weight reduction ranged from 14.7% to 24.2% in patients with HO and 25% to 32.6% in patients with HO. Among the patients with HO, 17 received RYGB and 8 patients received SG. The mean and SD of %TWL for HO at 24 months post-surgery was 21.47% ± 9.61%. The overall effect showed that patients with HO lose significantly less weight than patients with HO (mean difference: −7.65%, 95% Cl: −10.79%–−4.52%, P < 0.001, I2 = 0%), as shown in Fig. 3.
Forest plot of %TWL of patients with HO 24 months after bariatric surgery. (A) It represents the combined analysis. (B) It represents the subgroup analysis for RYGB. (C) It represents the subgroup analysis for SG.
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0493
Subgroup analysis showed a significant reduction in weight loss between HO and CO patients for SG (mean difference: −8.29, 95% Cl: −13.17–−3.40, P = 0 < 0.001, I 2 = 27%), and a non-SG significant reduction in weight loss for RYGB (mean difference: −6.41, 95% Cl: −12.96–0.14, P = 0.05, I2 = 72%). Garrez et al. (18) did not disclose subgroup data and their study was therefore left out of the analysis.
Total weight loss at 60 months after bariatric surgery
Two studies examined %TWL at 60 months after bariatric surgery, which accumulated 33 patients with HO and 142 CO controls. The mean weight reduction ranged from 17.8% to 22% in patients with HO and 26.2% to 29.5% in patients with HO. The mean and SD of %TWL for HO at 60 months post-surgery was 19.07 ± 16.12%. The overall effect showed that patients with HO lose significantly less weight than patients with HO (mean difference: −7.72%, 95% CI: −12.95%–−2.49%, P = 0.004, I²=0%), as shown in Fig. 4. Subgroup analysis was not conducted due to limited sample scale.
Forest plot of %TWL of patients with HO 60 months after bariatric surgery.
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0493
Discussion
Acquired HO leads to severe comorbidities including atherosclerotic cardiovascular disease, type 2 diabetes, and metabolic syndrome, and is distinctively refractory to conventional treatment (19). Weight-loss drugs have limited effect in controlling HO. Metformin, alone or with diazoxide, reduces insulin levels and body weight in adolescents with CP-related HO (−0.3 kg/m² vs +2.2 kg/m² pre-study) (8). Exenatide, a type of GLP-1 receptor agonist, has shown a significant reduction of body fat but not BMI in individuals with HO (10). Central nervous system agents including naltrexone (20) and phentermine (21) have been reported by some patients to be effective but there has been no specific evaluation of HO. Bariatric surgery is a promising option, achieving approximately 30%TWL at 12 months in common obesity (22). However, available studies on HO are few and limited in scale, which calls for a comprehensive meta-analysis on whether bariatric surgery works as well in HO as in CO.
One previous meta-analysis on this topic has been published since its inception. In their individual-level meta-analysis in 2013, Bretault et al. (23) reviewed a total of 21 cases and found significant weight loss at 6 months and 12 months after bariatric surgery (−20.86%TWL/6 months, −15.14%TWL/12 months). However, the meta-analysis was outdated, limited in included studies and did not assign CO comparisons.
This systematic review and meta-analysis examined all related literature until May 2024 and included four matched case-control studies, which added up to 52 CP-related HO cases and 286 CO controls. The result demonstrated that bariatric surgery significantly reduced weight for patients with HO (22.98 ± 14.22%TWL/12 months, 21.47 ± 9.61%TWL/24 months, 19.07 ± 16.12%/60 months), substantially surpassing exenatide, which had no significant impact on BMI. We noticed no significant difference between different types of surgeries.
Our meta-analysis also shows that bariatric surgery is significantly less effective in HO than in CO, the gap in weight reduction being −6.17%TWL/12 months, −6.41%TWL/24 months, −7.72%TWL/60 months, respectively. This is likely because hypothalamus feedback integrity is necessary for effective bariatric surgery. Dischinger et al. (24) reported that after bariatric surgery, patients with HO have higher GLP-1 levels and PYY levels but higher hunger ratings, suggesting unresolved hypothalamus-related hyperphagia. Peripheral changes following bariatric surgery might not adequately promote satiety or sustain long-term weight loss in patients with hypothalamic damage.
From a clinical perspective, this gap of effectiveness is important as patients with HO are usually at greater surgical risk, have more complex perioperative preparations and are prone to electrolyte disturbances such as hypernatremia (25). In addition, the application of bariatric interventions is limited in pediatric CP patients, which account for 30–50% of patients with HO (26). This irreversible surgery raises additional legal and ethical concerns in this minor group, who bears the risk of malnutrition and delayed development. The current Endocrine Society’s Clinical Practice Guideline for treating pediatric obesity (27) suggests that only adolescents with morbid obesity and advanced pubertal development, who have reached near-final or final height and are adherent to diet and exercise interventions, should be considered for bariatric surgery. It is also important to consider the postoperative complications of bariatric surgery, including iron-deficiency anemia, diarrhea and dumping syndrome following RYGB; folic acid and vitamin D deficiency, impaired effectiveness of oral desmopressin following SG; and dysphagia, vomiting following LAGB, all of which may have a more profound impact on patients with HO (28). As patients with HO have varying hypothalamic and pituitary functions, the net benefit from metabolic surgery in patients with HO is uncertain and they should be evaluated individually to decide whether to operate and which procedure.
Setmelanotide, a melanocortin 4 receptor (MC4R) agonist, previously known for treating congenital HO caused by POMC or LEPR deficiency (29), has recently completed its phase 2 trial on acquired HO and achieved a mean reduction in BMI of 15% ± 10% (30). The melanocortin pathway is composed of neurons in the hypothalamus activating the MC4R. When fed, peripheral leptin stimulates pro-opiomelanocortin (POMC) synthesis in the hypothalamus, which is then converted into melanocortin peptides that promotes satiety through activating MC4R (31). Hypothalamic injuries have been associated with reduction of leptin-melanocortin signaling, which maybe central in the mechanism of HO (32, 33). Distinct from traditional weight-loss drugs, setmelanotide targets hypothalamus dysregulation by amplifying the melanocortin pathway and restoring satiety (30). For patients of young age, setmelanotide might be a preferable option as it does not cause irreversible alteration to the digestive organs. As for adult patients, a synergistic approach combining setmelanotide and bariatric surgery may yield more sustainable weight loss.
Because CP is an extremely rare condition with an annual incidence rate of 0.13 to 2 per 100,000 population per year (34), it is difficult to conduct prospective studies or stratified comparative studies, and our thorough literature retrieval has yielded no such article on this topic. Nevertheless, our study emphasizes the limited effectiveness of bariatric surgery for patients with HO and calls for comparative studies on medication and bariatric surgery, as well as stratified studies on CP patients of different age group and levels of hypothalamus injury. Due to the varying efficacy of bariatric surgery in patients with HO and the significant side effects associated with the procedure, it is essential to develop a scoring system to help identify individuals who are suitable and necessary candidates for bariatric surgery, thereby maximizing the benefits for patients.
In summary, this study is the first systematic review with a meta-analysis of matched case-control studies on the effect of bariatric surgery in patients with HO. Our analysis indicates that each type of mainstream bariatric surgery, including SG, RYGB and BPD, can significantly reduce body weight, although the effects are less potent than in matched patients with CO. A multidisciplinary treatment plan using medications, surgery and lifestyle intervention may be more beneficial for patients with HO.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EC-24-0493.
Declaration of interest
There is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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