Edition 72 - February 2019 / Bibliographic Reviews

Bibliographic Reviews – Ed. 72

Marco A. Rivarola y Alicia Belgorosky

Servicio de Endocrinología, Hospital de Pediatria Garrahan, Buenos Aires, Argentina

We have selected the following publications for this issue of Endocrinología Pediátrica On line.

352

Springerplus. 2016 Sep 7;5(1):1508.

TNF-α gene polymorphisms and expression.

El-Tahan RR1, Ghoneim AM1El-Mashad N2.

1 Zoology Department, Faculty of Science, Damietta University, P.O. 34517, New Damietta, Damietta Egypt. 2 Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

Abstract

Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine with an important role in the pathogenesis of several diseases. Its encoding gene is located in the short arm of chromosome 6 in the major histocompatibility complex class III region. Most of the TNF-α gene polymorphisms are located in its promoter region and they are thought to affect the susceptibility and/or severity of different human diseases. This review summarizes the data related to the association between TNF-α gene and its receptor polymorphisms, and the development of autoimmune diseases. Among these polymorphisms the -308G/A TNF-α promotor polymorphism has been associated with the development of autoimmune diseases, however some discrepant results have been recorded. The other TNF-α gene polymorphisms had little or no association with autoimmune diseases. Current results about the molecules controlling TNF-α expression are also presented. The discrepancy between different records could be related partly to either the differences in the ethnic origin or number of the studied individuals, or the abundance and activation of other molecules that interact with the TNF-α promotor region, or other elements.

Comments.

TNF-α is thought to be involved in the regulation of many important cellular processes. It binds to two types of outer membrane receptors on the target cells, TNFR1 and TNFR2, and triggers the cell survival and pro-inflammatory NF-κB and MAP kinases activations (Locksley et al. 2001). The molecule activates phagocytes to engulf and clear infectious agents and cellular debris (Elahi et al. 2009). It also increases the expression of adhesion molecules on the vascular endothelium to allow immune cells, in particular neutrophils and macrophages, to translocate to the sites of tissue damage and infection (Barbara et al. 1996). TNF-α receptors (TNF-Rs) are active both in membrane-bound and soluble forms, and the soluble receptors act as physiological attenuators of TNF activity.

Association between TNF‑α genetic polymorphisms and some autoimmune diseases, such as systemic lupus erthymatosus (SLE), and rheumatoid arthritis (RA), have been reported. High concentrations of TNF-α were detected in serum and synovial fluid of RA patients and TNF-α blood concentration correlated with RA disease activity. The expression of TNF-α seems to be controlled by the activation of other cellular molecules including signal transducer molecules, nuclear factors and second messenger molecules. However, more studies to address the interaction between these molecules and TNF-α is required to finally map a clear TNF-α pathway. In summary, the expression of TNF-α seems to be controlled by the activation of other cellular molecules including signal transducer molecules, nuclear factors and second messenger molecules.

353

J Clin Endocrinol Metab. 2019 Jan 1;104(1):95-102.

Reducing the Number of Unnecessary Thyroid Biopsies While Improving Diagnostic Accuracy: Toward the “Right” TIRADS. Grani G1Lamartina L1Ascoli V2Bosco D2Biffoni M3Giacomelli L3Maranghi M1Falcone R1Ramundo V1Cantisani V4Filetti S1Durante C1.

1 Dipartimento di Medicina Interna e Specialità Mediche, Università di Roma “Sapienza,” Rome, Italy, 2 Dipartimento di Scienze Radiologiche, Oncologiche ed Anatomo Patologiche, Università di Roma “Sapienza,” Rome, Italy, 3 Dipartimento di Scienze Chirurgiche, Università di Roma “Sapienza,” Rome, Italy, 4 UOS Innovazioni Diagnostiche e Ultrasonografiche, Azienda Ospedaliera Universitaria Policlinico Umberto I, Università di Roma “Sapienza,” Rome, Italy.

Abstract

CONTEXT: The prevalence of thyroid nodules in the general population is increasingly high, and at least half of those biopsied prove to be benign. Sonographic risk-stratification systems are being proposed as “rule-out” tests that can identify nodules that do not require fine-needle aspiration (FNA) cytology. OBJECTIVE: To comparatively assess the performances of five internationally endorsed sonographic classification systems [those of the American Thyroid Association, the American Association of Clinical Endocrinologists, the American College of Radiology (ACR), the European Thyroid Association, and the Korean Society of Thyroid Radiology] in identifying nodules whose FNAs can be safely deferred and to estimate their negative predictive values (NPVs). DESIGN: Prospective study of thyroid nodules referred for FNA. SETTING: Single academic referral center. PATIENTS: Four hundred seventy-seven patients (358 females, 75.2%); mean (SD) age, 55.9 (13.9) years. MAIN OUTCOME MEASURES: Number of biopsies classified as unnecessary, false-negative rate (FNR), sensitivity, specificity, predictive values, and diagnostic ORs for each system. RESULTS: Application of the systems’ FNA criteria would have reduced the number of biopsies performed by 17.1% to 53.4%. The ACR Thyroid Imaging Reporting and Data System (TIRADS) allowed the largest reduction (268 of 502) with the lowest FNR (NPV, 97.8%; 95% CI, 95.2% to 99.2%). Except for the Korean Society of Thyroid Radiology TIRADS, all other systems exhibited significant discriminatory performance but produced significantly smaller reductions in the number of procedures. CONCLUSIONS: Internationally endorsed sonographic risk stratification systems vary widely in their ability to reduce the number of unnecessary thyroid nodule FNAs. The ACR TIRADS outperformed the others, classifying more than half the biopsies as unnecessary with a false negative rate of 2.2%.

Comments

The number of individuals harboring sonographically detected thyroid nodules continues to rise, with an estimated 219 million in the United States alone. The challenge for clinicians is to identify those rare nodules harboring a clinically relevant malignancy. Fine needle aspiration (FNA) has traditionally been used for this purpose. However, at least half of all biopsied nodules prove to be benign, and up to one third have cytological findings that are inconclusive.  Ultrasound-based risk-stratification systems have now been developed by many national and international thyroid societies but robust evidence is lacking on the relative strengths and weaknesses of the various systems.

For this study, Pre-FNA ultrasound examinations of the nodules was conducted in the Thyroid Cancer Unit of a large academic referral center. All patients consecutively referred to the unit for FNA cytology of a thyroid nodule between November 2015 and May 2018 were eligible for enrollment. Nodules were classified using five sonographic risk-stratification systems. A total of 832 thyroid nodules were subjected to sonographic risk stratification prior to FNA. The ultrasound examination identified 79 sub-centimeter nodules, which were excluded from the analysis because in the absence of particular clinical features. Of the 753 nodules measuring >1 cm, 251 were also excluded from the analysis because their reference standard diagnosis was inconclusive. The final cohort thus comprised 502 thyroid nodules identified in 477 patients (mean age, 56 years old; female/male ratio, 3.0). Thirty-six (7.2%) lesions met the reference standard criteria for malignancy. In 34 cases, the diagnosis was based on histologic findings: 27 papillary thyroid cancers, 1 follicular thyroid cancer, 2 medullary thyroid cancers, 1 anaplastic thyroid cancer, and 3 thyroid metastases from other malignancies. The remaining two were classified cytologically as TIR4/Bethesda V and managed with active surveillance alone. The sonographic risk-stratification tools assessed are basically “ruleout” tests, designed to identify nodules with low risks of malignancy whose cytologic assessment can safely be deferred. The goal was to compare the performances of five widely used systems of this type in achieving this goal. Each system assigns differential weights to the individual sonographic features evaluated to establish a nodule’s risk of malignancy, and the weight assigned to a given feature varies substantially from one system to another. The systems also differ from one another in terms of the size thresholds for identifying nodules within a given risk class that require FNA. In these cohorts, the number of biopsies performed would have been reduced to some extent if the decision had been based on strict application of any of the five internationally endorsed systems tested. However, the safest and most substantial reduction would have been achieved with the ACR TIRADS: it classified more than half of the biopsies ordered as unnecessary (268 of 502, 53.4%) and had the lowest FNR (false negative results) of all systems tested (6 of 268, 2.2%). Its abilities to exclude malignancy and to discriminate between benign and malignant nodules were substantially greater than those of its competitors (NPV (negative predictive value), 97.8%; DOR (diagnostic OR) 6.42; 95% CI, 2.62 to 15.72). The high number of planned biopsies identified by this system as unnecessary reflects the higher size thresholds it sets for recommending biopsy of nodules classified as low risk.

Importantly, the ACR TIRADS assigned all the thyroid nodules in the cohort to a risk class—a clear advantage over the widely used ATA system, which failed to classify a significant number of the nodules they studied (90, 17.9%) and of those analyzed by others. In their hands, the K-TIRADS performance was disappointing: the number of biopsies it would have eliminated was quite modest (86 of 502, 17.1%), and its discriminatory capacity was not statistically significant, as reflected by the lower end of the confidence interval of the AUROC (<0.5) and the DOR (<1). One small nodule classified as FNA deferrable by three of the five systems (the AACE/ACE/AME guidelines, the EU-TIRADS, and the ACR TIRADS) proved to be a medullary thyroid cancer. The sonographic features of these cancers are known to differ significantly from those of papillary thyroid cancer, which are the basis of sonographic risk stratification. One third of all medullary thyroid cancer have sonographic features (solid, round/ovoid shapes, smooth margins, mild hypoechogenicity) considered “low suspicion” in many systems: these features are sufficient to classify the nodule at least in the ATA intermediate suspicion pattern, requiring FNA when it measured >1 cm.

Importantly, however, the choice of a TIRADS system cannot be based solely on the number of biopsies it flags as unnecessary and its diagnostic accuracy. Inter observer variability and consistency over time are also important considerations, as are the setting in which it will be used (e.g., equipment, operator experience). Additionally, the US features being evaluated must also be defined in a manner that is clear and unambiguous to the operators using the system, an outcome favored by specific training and experience. The system must also be easy to use in routine clinical practice. For example, the ACR TIRADS differs from the other four systems tested in that it is based on a point scale rather than on pattern recognition. Points are assigned for five individual ultrasound features, and their sum determines the nodule’s risk class. This approach may be considered excessively time-consuming for use in daily practice.

The major strength of this study is its prospective nature: the US features of each nodule were evaluated during real time examinations carried out before aspirates were collected. In this setting, each of the five internationally endorsed TIRADS approaches evaluated, identified multiple thyroid nodules for which the request for FNA was probably unnecessary. Four of the five (AACE/ACE/AME, ATA, ACR TIRADS, and EU-TIRADS) showed a significant diagnostic value. The best overall performance was that of the ACR TIRADS, which classified more than half of the requested biopsies as unnecessary, with a negative predictive value (NPV) of 97.8%.

354

J Clin Endocrinol Metab. 2019. Volume 104, Feb, Pages 241–249

Algorithms to Define Abnormal Growth in Children: External Validation and Head-To-Head Comparison. 

Scherdel1,2S. Matczak3J. Léger4C. Martinez-Vinson5O. Goulet6; R. Brauner7 , S. Nicklaus S8Resche-Rigon M9Chalumeau M2,3Heude B1.

1INSERM, UMR1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center, Early Origins of the Child’s Health and Development Team, Paris Descartes University, Villejuif, France. 2INSERM, UMR1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center, Obstetrical, Perinatal, and Pediatric Epidemiology Research Team, Paris Descartes University, Paris, France.3Department of General Pediatrics, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France. 4Department of Pediatric Endocrinology and Diabetology, Robert-Debré Hospital, Assistance Publique-Hôpitaux de Paris, Paris Diderot University, Reference Centre for Endocrine Growth and Development Diseases, Paris, France. 5Department of Pediatric Gastroenterology and Nutrition, Robert-Debré Hospital, Assistance Publique-Hôpitaux de Paris, Paris-Diderot University, Paris, France.6Department of Pediatric Gastroenterology-Hepatology and Nutrition, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France. 7Unité d’Endocrinologie Pédiatrique, Fondation Ophtalmologique Adolphe de Rothschild, Paris Descartes University, Paris, France.8Centre des Sciences du Goût et de l’Alimentation, AgroSupDijon Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Université Bourgogne Franche-Comté, Dijon, France. 9INSERM, UMR1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center, Epidémiologie Clinique, Statistique, pour la Recherche en Santé, Service de Biostatistique et Information Médicale, Saint-Louis Hospital, Paris Diderot University, Paris, France.

Abstract 

BACKGROUND: Growth monitoring of apparently healthy children aims at early detection of serious conditions by use of both clinical expertise and algorithms that define abnormal growth. OBJECTIVE: An external validation study with head-to-head comparison of the seven algorithms combined with study of the impact of use of the World Health Organization (WHO) vs national growth charts on algorithm performance. DESIGN: With a case-referent approach, authors retrospectively applied all algorithms to growth data for children with Turner syndrome, GH deficiency, or celiac disease (n = 341) as well as apparently healthy children (n = 3406). Sensitivity, specificity, and theoretical reduction in time to diagnosis for each algorithm were calculated for each condition by using the WHO or national growth charts. RESULTS: Among the two with high specificity (>98%), the Grote clinical decision rule had higher sensitivity than the Coventry consensus (4.6% to 54% vs 0% to 8.9%, P < 0.05) and offered better theoretical reduction in time to diagnosis (median: 0.0 to 0.9 years vs 0 years, P < 0.05). Sensitivity values were significantly higher with the WHO than national growth charts at the expense of specificity. CONCLUSION: The Grote clinical decision rule had the best performance for early detection of the three studied diseases, but its limited potential for reducing time to diagnoses suggests the need for better-performing algorithms based on growth charts.

Comments.

Seven algorithms have been proposed to define abnormal stature growth. Some are based on straightforward unique thresholds and others on more complex combinations of auxological parameters: WHO criterion (37), Coventry consensus (38), Dutch consensus (39), GHRS criteria (40), Grote clinical decision rule (17), Saari clinical decision rule for Turner syndrome (19), Saari clinical decision rule for celiac disease (3)

Author´s Discussion:

Among the seven algorithms proposed for defining abnormal growth, the Grote clinical decision rule had the best performance, with specificity greater than 98% and sensitivity from 42% to 54% depending on the studied target conditions. Sensitivity was higher with the WHO than national growth charts at the expense of specificity. The transportability of these results in terms of sensitivity should be further analyzed for children with other targeted diseases of growth monitoring, such as Crohn disease and craniopharyngioma. Nonetheless, the sensitivity of the Grote clinical decision rule remains low, with limited potential for theoretical reduction in time to diagnosis. Studies are needed to obtain better algorithms for improving this sensitivity without losing too much specificity.

355

J Clin Endocrinol Metab. 2019 Mar 1;104(3):658-664. doi: 10.1210/jc.2018-01133.

Risk of Meningioma in European Patients Treated With Growth Hormone in Childhood: Results From the SAGhE Cohort.

Swerdlow AJ1,2Cooke R1Beckers D3,4Butler G5,6Carel JC7,8Cianfarani S9,10Clayton P11,12Coste J13,14Deodati A9, Ecosse E13,14Hokken-Koelega ACS15,16Khan AJ11,12Kiess W17Kuehni CE18Flück CE19Pfaffle R17Sävendahl L10Sommer G18Thomas M4Tidblad A10, Tollerfield S5Zandwijken GRJ15,16.

1 Institute of Cancer Research, Division of Genetics and Epidemiology, London, United Kingdom. 2 Institute of Cancer Research, Division of Breast Cancer Research, London, United Kingdom. 3 Unite d’Endocrinologie Pédiatrique, Centre Hospitalier Universitaire Université Catholique de Louvain Namur, Yvoir, Belgium. 4 Belgian Society for Pediatric Endocrinology and Diabetology, Brussels, Belgium. 5 University College London Institute of Child Health, London, United Kingdom. 6 University College London Hospitals National Health Service Foundation Trust, London, United Kingdom. 7 Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert-Debré, Department of Pediatric Endocrinology and Diabetology, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Paris, France. 8 Promoting Research Oriented Towards Early CNS Therapies, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. 9 Dipartimento Pediatrico Universitario Ospedaliero “Bambino Gesù” Children’s Hospital-Tor Vergata University, Rome, Italy. 10 Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden. 11 Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom. 12 Developmental Biology and Medicine, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, United Kingdom. 13 Biostatistics and Epidemiology Unit and Approches Psychologiques et Epidémiologiques des Maladies Chroniques Equipe d’Accueil, Paris, France. 14 Groupe Hospitalier Cochin-Saint Vincent de Paul and University Paris Descartes, Paris, France. 15 Dutch Growth Research Foundation, Rotterdam, Netherlands. 16 Erasmus Medical Center/Sophia Children’s Hospital, Rotterdam, Netherlands. 17 Hospital for Children and Adolescents and Centre of Pediatric Research, University of Leipzig, Leipzig, Germany. 18 Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. 19 Division of Paediatric Endocrinology, Diabetology, and Metabolism, University Children’s Hospital Bern, Inselspital, Bern, Switzerland.

Abstract

CONTEXT: There has been concern that GH treatment of children might increase meningioma risk. Results of published studies have been inconsistent and limited. OBJECTIVE: To examine meningioma risks in relation to GH treatment. DESIGN: Cohort study with follow-up via cancer registries and other registers. SETTING: Population-based. PATIENTS: A cohort of 10,403 patients treated in childhood with recombinant GH in five European countries since this treatment was first used in 1984. Expected rates from national cancer registration statistics. MAIN OUTCOME MEASURES: Risk of meningioma incidence. RESULTS: During follow-up, 38 meningiomas occurred. Meningioma risk was greatly raised in the cohort overall [standardized incidence ratio (SIR) = 75.4; 95% CI: 54.9 to 103.6], as a consequence of high risk in subjects who had received radiotherapy for underlying malignancy (SIR = 658.4; 95% CI: 460.4 to 941.7). Risk was not significantly raised in patients who did not receive radiotherapy. Risk in radiotherapy-treated patients was not significantly related to mean daily dose of GH, duration of GH treatment, or cumulative dose of GH. CONCLUSIONS: Our data add to evidence of very high risk of meningioma in patients treated in childhood with GH after cranial radiotherapy, but suggest that GH may not affect radiotherapy-related risk, and that there is no material raised risk of meningioma in GH-treated patients who did not receive radiotherapy.

Comments

There has been concern as to whether GH therapy might increase cancer risks. Meningiomas express GH receptors, and in vitro activation of the GH/IGF-1 axis increases the growth rate of meningiomas.

In the US Childhood Cancer Survivors Study cohort, second malignancy was significantly more common among GH treated than non–GH-treated patients, and meningioma was the most common second malignancy in the GH-treated group, accounting for 40% of all second neoplasms. To analyze the risk with greater power, authors analyzed meningioma risks in the Europe SAGhE study, a large cross-European cohort study of patients treated with r-hGH.

This was a consequence of a risk six times greater in the subset of patients who had received GH after treatment of cancer, and within these, greater risk in the patients who had received cranio (-spinal) radiotherapy.

However, the main reason for the raised meningioma risk in the cohort is likely to be ionizing radiation exposure. Previous cohort studies of meningioma risk after radiation exposure have found excess relative risks per Gy. In conclusion, these data add to evidence of the high relative risks of meningioma in patients treated in childhood with r-hGH after cranial radiotherapy for malignancy. Clinically it is important to be aware of this risk when following up such patients. These data and the previous literature on radiation effects indicate that the raised risk is mainly due to radiotherapy, although it may also to some extent reflect detection of asymptomatic meningiomas as a consequence of intensive medical surveillance and cerebral imaging in these patients. These data also suggest, however, that GH treatment has not augmented further the radiotherapy-related risk.

356

Horm Res Paediatr. 2018, 90(4):275-282. doi: 10.1159/000492128.

Accelerated Pubertal Tempo in a 46,XY Aromatase-Deficient Patient.

Costanzo M1, Garcia-Feyling J2, Saraco N1,3, Marino R1, Pérez Garrido N1, Touzon MS1, Viterbo G1, Lazzati JM1, Patiño HC1, Mattone C1, Maceiras M1, Belgorosky A1,3, Guercio G1,3.

1Servicio de Endocrinología, Hospital de Pediatría Garrahan, Buenos Aires, Argentina 2 Hospital Regional de Concepción, Tucumán, Argentina. 3Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina, abelgo12345@gmail.com.

Abstract

BACKGROUND: Aromatase deficiency is a rare autosomal recessive disorder. 46,XY-affected patients often remain undiagnosed until late puberty. Only 2 pediatric cases have been reported. Data on pubertal development in affected males are scarce. AIM: To report the clinical phenotype and hormonal studies of an aromatase-deficient boy during the prepubertal and early pubertal period. RESULTS: The patient was the older brother of a 46,XX girl with aromatase deficiency. Molecular analysis revealed a previously reported homozygous mutation (Arg192Cys) in the CYP19A1 gene. Pubertal onset was at 9.8 years. At 11.3 years of age, signs of rapidly progressive puberty were seen. Laboratory tests revealed normal pubertal basal and GnRH-stimulated gonadotropin levels, normal Sertoli cell markers, and increased testosterone. The prepubertal lumbar spine bone mineral density (BMD) was normal but pubertal bone mineral accrual was incomplete, leading to osteopenia. CONCLUSION: Estrogen restraint on gonadotropin secretion has been demonstrated in animal and human models. Interestingly, our patient presented with accelerated puberty and apparently normal pituitary gonadal function. These findings suggest that aromatase activity may be required to define pubertal progression in boys. Estrogen deficiency due to aromatase deficiency is responsible for insufficient bone mineral accrual during puberty.

Comments

Hormonal studies conducted in aromatase-deficient boys and the case reported here showed normal basal and GnRH-stimulated gonadotropin levels and normal serum inhibin B and AMH during infancy and prepuberty. These findings suggest that in normal boys estrogens do not seem to play an important role in the regulation of gonadotropin secretion during these periods

Interestingly, our aromatase-deficient patient presented with accelerated progression of secondary sexual characteristics and apparently normal pituitary gonadal function. The time between pubertal onset and Tanner stage 4 (G4 and PH4) was 1.5 years. The progression of genital virilization in early puberty was consistent with the significant increase in basal serum testosterone levels, which were higher than expected for his age and for the Tanner stage.

This finding suggests that, at least during prepubertal and pubertal years, the lack of estrogens might not affect glucose homoeostasis or the lipid metabolism. In line with these observations, the use of aromatase inhibitors in pubertal boys has been associated with neutral or even beneficial effects on insulin sensitivity, while even short-term use in adult men has been associated with a decrease in insulin sensitivity. This finding emphasizes the important role of estrogens in bone mass acquisition during male puberty. Even though aromatase deficiency is a recessive disorder, more affected females (n = 26) than males (n = 12) have been reported. The underrepresentation of 46,XY patients might be explained by the lack of significant findings in the first decades of life that could delay or impair diagnosis. Rapid pubertal progression may be an additional feature in the phenotype of male aromatase deficiency that could be useful to improve the identification of affected boys who are currently underdiagnosed.

In summary, aromatase deficiency is a useful human model to evaluate the role of estrogens in the regulation of gonadotropin secretion as was previously described. The accelerated pubertal progression observed in this 46,XY aromatase-deficient patient suggests that aromatase activity may be involved in the male pubertal tempo. Interestingly, the finding of rapid progression of secondary sexual characteristics in a boy may be an early sign that should alert the physician to consider aromatase deficiency, especially when delayed bone age is associated.

 

357

(J Clin Endocrinol Metab 103: 370–375, 2018)

Oxytocin and Naltrexone Successfully Treat Hypothalamic Obesity in a Boy Post-Craniopharyngioma Resection.  

Eugenie A. Hsu1, Jennifer L. Miller2 Francisco A. Perez,3 and Christian L. Roth4,5

1Department of Psychiatry, Kaiser Permanente Medical Center, Oakland, California 94611; 2Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, Florida 32611; 3Department of Radiology, Seattle Children’s Hospital and Research Institute, Seattle, Washington 98145; 4Center for Integrative Brain Research, Seattle Children’s Hospital and Research Institute, Seattle, Washington 98101; and 5Department of Pediatric Endocrinology, Seattle Children’s Hospital and Research Institute, Seattle, Washington 98145

CONTEXT: Hypothalamic obesity, a treatment-resistant condition common to survivors of craniopharyngioma (CP), is strongly associated with a poor quality of life in this population. Oxytocin (OT), a hypothalamic neuropeptide, has been shown to play a role in the regulation of energy balance and to have anorexigenic effects in animal studies. Naltrexone (NAL), an opiate antagonist, has been shown to deter hedonic eating and to potentiate OT’s effects. DESIGN: In this parent-observed study, authors tested the administration of intranasal OT for 10 weeks (phase 1), followed by a combination of intranasal OT and NAL for 38 weeks (phase 2) in a 13-year old male with confirmed hypothalamic obesity and hyperphagia post-CP resection. Treatment resulted in 1) reduction in body mass index (BMI) z score from 1.77 to 1.49 over 10 weeks during phase 1; 2) reduction in BMI z score from 1.49 to 0.82 over 38 weeks during phase 2; 3) reduced hyperphagia during phases 1 and 2; 4) continued hedonic high-carbohydrate food-seeking in the absence of hunger during phases 1 and 2; and 5) sustained weight reduction during decreased parental monitoring and free access to unlocked food in the home during the last 10 weeks of phase 2. CONCLUSION: This successful intervention of CP-related hypothalamic obesity and hyperphagia by OT alone and in combination with NAL is promising for conducting future studies of this treatment recalcitrant form of obesity.

Comments

Considered a serious morbidity that often contributes to the poor quality of life of craniopharyngioma (CP) survivors, hypothalamic obesity (HO) is a severe obesity syndrome with very limited treatment options and poor outcomes. Highly prevalent in CP survivors, pan-hypopituitarismis treated with hormone therapy to replace several hypothalamic and pituitary hormone deficiencies. However, oxytocin (OT), a hypothalamic neuropeptide, is not typically replaced due to a lack of evidence of its medical necessity. Among individuals with Prader-Willi syndrome who share many phenotypic traits with CP survivors, including social impairment, obesity, and hyperphagia, low-dose intranasal OT administration demonstrated multiple benefits, including reduction in appetite drive.

The cortico-limbic and meso-limbic systems play a central role in regulation of eating behavior by mediating the rewarding aspects of food, and naltrexone (NAL), an opiate antagonist, has been shown to decrease subjective food pleasantness, eating rate, and appetite in obese men. Studies in animals show NAL’s effect on reducing binge-like hyperphagia of highly palatable foods. In addition, opioids are known to decrease OT whereas opiate antagonists, conversely, have been shown to increase the release of OT and potentiate the effects of OT.

Case description: At age 8, patient S underwent a transcranial gross total resection of a tumor identified as a multicystic and solid CP. No radiation treatment was performed. After the resection, S was diagnosed with visual impairment, adipsic diabetes insipidus, adrenal insufficiency, thyroid deficiency, and growth hormone deficiency. In addition to panhypopituitarism, S developed hyperphagia and obesity soon after his tumor resection. Similar to the experiences of many CP survivors, S exhibited pathological eating behaviors. Examples of S’s pretreatment hyperphagia included frequent complaints of hunger, middle-of-the-night eloping for food, stealing food, and stashing food. By MRI there was evidence of injury to the floor of the third ventricle and bilateral anterior hypothalamus, including the region of the paraventricular nuclei and supra-optic nuclei. There was also evidence of at least unilateral injury to the medial and posterior hypothalamus, including the region of the arcuate nucleus.

Initial 10-week OT treatment

At the outset of OT treatment, S’s panhypopituitarism symptoms were treated with full replacement doses of desmopressin, hydrocortisone, levothyroxine, liothyronine, and growth hormone. Additionally, S took fish oil for hyperlipidemia, and 6 mg/night melatonin and 5 mg/d dextroamphetamine for his disrupted circadian rhythm and daytime somnolence, respectively. Four months after starting OT treatment, S began receiving subcutaneous 24 mg/wk testosterone to induce puberty due to hypogonadotropic hypogonadism. Due to his poor response to 6 mg/night, S’s melatonin dose was lowered to 0.3 mg/night 7 months after starting OT.

Thirty days before starting the therapeutic dose, S was 170 cm tall and weighed 77 kg; his BMI z score was 1.77 standard deviation score (SDS) (96th percentile). After 10 weeks of treatment, he was 171 cm tall and weighed 72.6 kg; he lost 4.4 kg, and his BMI z score dropped to 1.49 SDS (93rd percentile). S also demonstrated noticeable qualitative changes in the areas of improved satiety (leaving food unfinished), decreased urgency to eat (tolerating longer intervals between snacks and meals), and overall decreased food preoccupation (talking less often about food, insisting less on being in the kitchen). Despite these improvements, when an opportunity arose to attain highly palatable foods (e.g., cookies and candy), he continued surreptitious food-seeking of these types of food.

Opioid receptor antagonists, such as NAL, can reduce the reinforcing values of food and food-related rewards. In a study of NAL’s effect on cerebrospinal humans, Gordon et al. (J Endocr Soc. 2017) found that agouti-related protein and cortisol stimulation by NAL may mitigate hypothalamic proopiomelanocortin-induced decrease in food intake. Cravings for both food and drugs are strongly linked; both hedonic food and drug seekers share a common disruption in dopaminergic pathways. In studies on recently abstinent alcoholics treated with NAL, elevated plasma concentrations of cortisol and adrenocorticotropic hormone and the plasma concentrations of cortisol correlated negatively with the level of alcohol craving. These studies suggest that NAL’s effect on the reduction of food and alcohol craving might be related to its ability to activate the HPA axis and may be argued to explain NAL’s failure to deter hedonic food-seeking given S’s panhypopituitarism and nonintact HPA axis. Nevertheless, NAL may have potentiated the therapeutic effects of OT by stimulating the release of existing amounts of endogenous OT.

Conclusion. The successful and sustained reduction of weight and hyperphagia using OT and additional NAL was demonstrated in a boy with HO secondary to CP. The dearth of clinical trials using OT and NAL, the lack of effective treatment options, and the resultant poor quality of life for this population compels future research on this promising intervention for this difficult-to-treat obesity syndrome. Moreover, given the public health crisis posed by the explosive rates of worldwide obesity and its associated high morbidity, this well-tolerated and successful intervention on such a treatment-recalcitrant syndrome motivates further study on other more common forms of obesity.

OT has been shown to have anorexigenic effects in humans and animals. The anorexigenic effects of exogenous OT treatment are thought to be multifactorial in nature.


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