Jens Aberle

Genetic variation may influence obesity only under conditions of diet: Analysis of three candidate genes

Under the hypothesis of obesity as a polygenetic disease numerous genes have been associated with an obese phenotype and metabolic co-morbidities. The cannabinoid receptor 1 (CB 1) is part of an underinvestigated system that participates in appetite control. Previous publications suggest that the endocannabinoid systems interact with the better understood leptin-melanocortin axis. Neuropeptide Y (NPY) is a player in the latter. Finally resistin has been shown to influence NPY expression in the brain. In a cohort of 1721 caucasion men and women with a BMI of 25kg/m(2) or more we therefore investigated three candidate polymorphisms at baseline and following 3 months low fat caloric restriction diet by polymerase chain reaction and restriction digestion: the 1359 G/A variant of the cannabinoid receptor 1 (CB1), the L7P variation in neuropeptide Y (NPY) and the -420C>G polymorphism in resistin. Comparing groups according to genotype for each gene separately revealed significant results at baseline only for the CB1 gene. However, upon dieting significant data was found for all 3 genes. Carriers of at least one A allele in CB1 lost more weight and reduced LDL cholesterol more than wildtype patients. LL homocygotes in NPY had a greater reduction in glucose, triglycerides, and LDL cholesterol whereas in resistin carriers of the G allele had a greater reduction in weight and triglycerides. Creating two groups defined by NPY and resistin genotype, respectively, with similar BMI values resulted in significant differences concerning weight loss and metabolic improvement. In conclusion, genetic polymorphisms associated with obesity may become relevant only under the condition of a low calory diet. The presence of a certain genotype may then be beneficial for obesity treatment.

Surgery for pediatric craniopharyngiomas: is less more?

Abstract Surgery for craniopharyngiomas, especially in childhood and adolescence, has evolved from an era of aggressive strategies – with the primary goal of gross total removal and accepting an impaired functional outcome – to a more individually tailored therapy that avoids immediate treatment-related and long-term morbidity. Modern imaging techniques and a wider understanding of hypothalamic risk factors have led to surgical strategies adapted to the localization of these inhomogenously grown pathologies. Whereas purely infradiaphragmatic as well as supradiaphragmatic/infrachiasmatic tumors have a favorably surgical outcome with higher gross total resection rates in experienced hands, lesions within the third ventricle extending beyond the mammillary bodies remain a problem. The same is valid for lesions beyond 3 cm in diameter, more or less independent of their localization. Aside from the traditional microscopic approach via the subfrontal or pterional craniotomy, transsphenoidal approaches and other minimal invasive surgical methods, e.g., catheter implantation into cystic formations of the tumor have become popular. Radiotherapy, with its risks and limitations, can effectively be added to avoid recurrences. Nowadays, surgery as part of an interdisciplinary treatment strategy is still the typical first choice. However, taking the patient’s long-term prognosis into considertaion, the surgical complication rates have to be minimized.

CSF fistulas after transsphenoidal pituitary surgery--a solved problem?

OBJECTIVE Transsphenoidal surgery has been the gold standard for intra- and suprasellar lesions as well as some extrasellar pathologies for more than 40 years. This approach, with proper surgical expertise, is very safe with a low morbidity and mortality rate. However, as with every surgical treatment, complications can occur and may result in serious consequences for the patient. The goal of this article is to focus on cerebrospinal fluid (CSF) fistulas after transsphenoidal surgery and discuss possible risk factors and treatment options, including less common procedures in persistent CSF fistulas. METHODS Over a period of 24 months, 339 consecutive patients underwent a total of 363 transsphenoidal surgeries for different pathologies in our institution. There were 282 patients with pituitary adenomas and 57 patients with nonadenomateous lesions. RESULTS CSF fistulas occurred in total of six patients (1.77%), most frequently after surgery for nonadenomateous lesions (7%). The rate was only 0.7% after surgery for pituitary adenomas. In three patients, a simple resurgery with repacking of the sella using muscle, fat, and fibrin glue was performed. All three patients received a lumbar drainage for 5 days as well. All three patients had recurrent CSF fistulas despite surgical repair, requiring multiple resurgeries. In two patients, the implantation of a ventriculoperitoneal (vp) shunt with programmable valve for continuous lowering of the CSF pressure was required. In both patients, the vp shunt was explanted 2 to 3 months after the last proven rhinorrhea. Out of the 339, 2 patients developed meningitis due to CSF fistulas (0.59%). CONCLUSIONS CSF fistulas continue to present a problem after transsphenoidal surgery and require sophisticated technical measures to treat this complication. Failure after repair can occur and necessitates more intense treatment modalities. The usage of the transsphenoidal approach in other skull base lesions leads to higher rates of CSF fistulas and subsequently higher frequency of meningitis.

Metformin after bariatric surgery--an acid problem.

Metformin is the oral drug of first choice in type 2 diabetes. Therefore a large number of patients undergoing bariatric surgery will be on Metformin treatment. However, use of Metformin has been associated with lactate acidosis. Weight loss following bariatric surgery is most pronounced during the first weeks after the operation and this creates a phase of negative energy balance with ketone body formation. To shed more light on this situation we measured ketone bodies in 90 patients 5 days-18 months after bariatric surgery. Ketone bodies were markedly elevated during the first 3-4 months. Metformin use should therefore be critically reconsidered after bariatric operations.

Cushing's Syndrome Due to a Corticotropin-Releasing Hormone- and Adrenocorticotrophic Hormone-Producing Neuroendocrine Pancreatic Tumor

OBJECTIVE To our knowledge, only 2 cases of pancreatic neuroendocrine tumors have been described as the source of corticotropin-releasing hormone (CRH) in Cushings syndrome. Here, we describe a case of ectopic adrenocorticotrophic hormone (ACTH-) and CRH-production caused by a pancreatic neuroendocrine tumor. METHODS We analyzed and summarized the patients medical history, physical examination results, laboratory data, imaging studies, and histopathologic results. RESULTS An endocrinologic workup revealed massive ACTH-dependent hypercortisolism. Pituitary magnetic resonance imaging (MRI) showed no pathologic findings and led to extensive imaging in search of the suspected ectopic lesion. Ketoconazole treatment was initiated. Rapid deterioration of the patients clinical condition due to escalating cortisol levels and resulting sepsis required an emergency adrenalectomy to control the hypercortisolism. A positron emission tomography-computed tomography (PET-CT) scan revealed a hepatic lesion, which was biopsied. Histology of the lesion showed a well-differentiated endocrine tumor. Subsequent scintigraphy with octreotide (a somatostatin [SMS] analog) detected a pancreatic tumor, which was endosonographically confirmed. The initiated SMS therapy was followed by a distal splenopancreatectomy and a right hemihepatectomy. Immunostaining of the specimen showed positive expression for CRH and ACTH. CONCLUSION We conclude that SMS-scintigraphy did have an additional diagnostic benefit compared to PET-CT. In hypercortisolemic patients, rapid endocrinologic evaluation is crucial to prevent rapid deterioration and a possible fatal outcome.

Resequencing the APOE gene reveals that rare mutations are not significant contributory factors in the development of type III hyperlipidemia

BACKGROUND APOE (apolipoprotein E gene) 2/2 genotype and an apolipoprotein B/total cholesterol (ApoB/TC) ratio <0.15 are diagnostic for type III hyperlipidemia. We hypothesized that patients with APOE genotype 2/3 or 2/4 and an ApoB/TC ratio <0.15 may have a mutation in their epsilon 3 or 4 allele, resulting in a type III hyperlipidemia phenotype. OBJECTIVE We tested this hypothesis. METHODS The DNA sequence of all 4 exons and exon/intron boundaries of the APOE (plus 600 bp upstream of exon 1) of 47 patients with APOE 2/3 and 18 patients with APOE 2/4 genotype and an ApoB/TC ratio <0.15 was determined. As controls the APOE sequence of 53 APOE genotype 2/3 and 20 APOE genotype 2/4 probands with ApoB/TC ratio >0.15 was determined. The sequence analysis was extended to include 47 patients with APOE genotype 3/3, 14 with APOE genotype 3/4, and 3 with APOE genotype 4/4 and an ApoB/TC ratio <0.15. Finally, we determined the sequence of the APOE gene in 145 patients with an ApoB/TC ratio >0.15 and who had triglycerides above the 90th percentile for age and sex. RESULTS No deleterious variants in the APOE gene were observed in patients with APOE genotype other than 2/2 and an ApoB/TC ratio <0.15. Only a single probably deleterious variant, K72E, was observed in patients with triglycerides above the 90th percentile. CONCLUSIONS Patients with an ApoB/TC ratio <0.15 do not have an increased likelihood of mutation in the APOE gene, and rare variants in the APOE gene are not important in the development of hypertriglyceridemia.

The relative importance of common and rare genetic variants in the development of hypertriglyceridemia.

Plasma lipid levels are a complex trait with a genetic and an environmental component. There are two models for the genetic basis of complex traits: the common-disease common-variant hypothesis, in which susceptibility is due to variants occurring at relatively high frequency but low effect size; and the common-disease rare-variant hypothesis, where disease is due to multiple rare variants each occurring at low frequency but with high effect size. Genome-wide association studies have identified a number of common variants associated with plasma lipid levels. However, they account for only a proportion of the genetic variance. Resequencing studies are revealing the importance of rare variants in accounting for the missing variance. Next-generation sequencing will allow the relative importance of the two hypotheses to be assessed.

Cavernous sinus sampling in patients with Cushing's disease

OBJECT Correct diagnosis and precise localization of adenomas in patients with Cushings disease are essential for avoiding unsuccessful transsphenoidal pituitary exploration. In addition to the well-established inferior petrosal sinus sampling, preoperative cavernous sinus sampling (CSS) was introduced as a potentially improved way to predict adenoma lateralization. The authors present their results with CSS in a consecutive series of patients with Cushings disease. METHODS During 1999-2014, transsphenoidal surgeries were consecutively performed in 510 patients with Cushings disease. For most patients, suppression of cortisol in high-dose dexamethasone tests and stimulation of adrenocorticotropic hormone and cortisol after administration of corticotropin-releasing hormone were sufficient to prove the diagnosis of adrenocorticotropic hormone-dependent hypercortisolism. Of the 510 patients, 67 (13%) were referred to the department of neuroradiology for CSS according to the technique of Teramoto. The indications for CSS were unclear endocrine test results or negative MRI results. Data for all patients were retrospectively analyzed. RESULTS A central/peripheral gradient was found in 59 patients; lateralization to the left or right side was found in 51. For 8 patients with a central/peripheral gradient, no left/right gradient could be determined. For another 8 patients with equivocal test results, no central/peripheral gradient was found. No severe CSS-associated complications were encountered. Of the 51 patients who underwent transsphenoidal surgery, the predicted lateralization was proven correct for 42 (82%). CONCLUSIONS As MRI techniques have improved, the number of potential candidates for this invasive method has decreased in the past decade. However, because detecting minute adenomas remains problematic, CSS remains a useful diagnostic tool for patients with Cushings disease.

Off-label antiobesity treatment in patients without diabetes with GLP-1 agonists in clinical practice.

The aim of the work was to investigate whether continuation of treatment, side effects, and effect on weight loss of GLP-1 agonists in obese patients without diabetes are equally promising in daily clinical-practice-settings compared to controlled clinical trials. Obese patients without diabetes of our interdisciplinary obesity centre were treated off-label with GLP-1-agonists for different time periods. Application was started with low-dose and increased if side effects were tolerable. Monthly costs were € 125 for daily applications of 1.2 mg liraglutide or 10 μg exenatide twice daily. Data were obtained by telephone interviews about baseline characteristics, weight loss, sensation of satiation, duration of therapy, side effects, and reasons for discontinuation. Of 43 included cases (5 males, mean age 43±11 years, mean weight 107±24 kg, mean excess weight 35±21 kg) 7 were treated with exenatide and 36 with liraglutide. Excess weight loss in linear regression models was 6.7% per month (p <0.05) under control of age, sex, initial weight, and type of GLP-1 analogue treatment and did not significantly differ between liraglutide and exenatide. Overall, 58% of patients reported side effects mostly concerning the gastrointestinal tract. Surprisingly no patient reported vomiting. One patient developed a severe pancreatitis. At time of telephone interview only 30.2% were continuing treatment. Mean treatment duration was 2.98±2.71 months. Common reasons for discontinuation of treatment were no/little effect on weight loss (27.9%), intolerable side effects (20.9%), or financial reasons (14%). GLP-1 agonist treatment in obese patients without diabetes also correlates with significant weight loss in clinical practice. However, side effects and discontinuation of treatment are common. Therefore, long-term effect on weight loss might not be as promising as suggested by data from clinical trials.

Preventive medicine for von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.