Hypertrophy in the Distal Convoluted Tubule of an 11β-Hydroxysteroid Dehydrogenase Type 2 Knockout Model

Na⁺ transport in the renal distal convoluted tubule (DCT) by the thiazide-sensitive NaCl cotransporter (NCC) is a major determinant of total body Na⁺ and BP. NCC-mediated transport is stimulated by aldosterone, the dominant regulator of chronic Na⁺ homeostasis, but the mechanism is controversial. Transport may also be affected by epithelial remodeling, which occurs in the DCT in response to chronic perturbations in electrolyte homeostasis. Hsd11b2^−/− mice, which lack the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) and thus exhibit the syndrome of apparent mineralocorticoid excess, provided an ideal model in which to investigate the potential for DCT hypertrophy to contribute to Na⁺ retention in a hypertensive condition. The DCTs of Hsd11b2^−/− mice exhibited hypertrophy and hyperplasia and the kidneys expressed higher levels of total and phosphorylated NCC compared with those of wild-type mice. However, the striking structural and molecular phenotypes were not associated with an increase in the natriuretic effect of thiazide. In wild-type mice, Hsd11b2 mRNA was detected in some tubule segments expressing Slc12a3, but 11βHSD2 and NCC did not colocalize at the protein level. Thus, the phosphorylation status of NCC may not necessarily equate to its activity in vivo, and the structural remodeling of the DCT in the knockout mouse may not be a direct consequence of aberrant corticosteroid signaling in DCT cells. These observations suggest that the conventional concept of mineralocorticoid signaling in the DCT should be revised to recognize the complexity of NCC regulation by corticosteroids.     

Nutritional Deficiencies in Morbidly Obese Patients: A New Form of Malnutrition?

Even though in the Western world there is almost no limitation to a wide variety of food supply, nutritional deficiencies can be found in both normal-weight population and in the obese population. In this review, we examine the prevalence and manifestations of various mineral deficiencies in obese patients.     

Prenatal Programming of Metabolic Syndrome in the Common Marmoset Is Associated With Increased Expression of 11��-Hydroxysteroid Dehydrogenase Type 1

OBJECTIVE

Recent studies in humans and animal models of obesity have shown increased adipose tissue activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which amplifies local tissue glucocorticoid concentrations. The reasons for this 11β-HSD1 dysregulation are unknown. Here, we tested whether 11β-HSD1 expression, like the metabolic syndrome, is “programmed” by prenatal environmental events in a nonhuman primate model, the common marmoset monkey.

RESEARCH DESIGN AND METHODS

We used a “fetal programming” paradigm where brief antenatal exposure to glucocorticoids leads to the metabolic syndrome in the offspring. Pregnant marmosets were given the synthetic glucocorticoid dexamethasone orally for 1 week in either early or late gestation, or they were given vehicle. Tissue 11β-HSD1 and glucocorticoid receptor mRNA expression were examined in the offspring at 4 and 24 months of age.

RESULTS

Prenatal dexamethasone administration, selectively during late gestation, resulted in early and persistent elevations in 11β-HSD1 mRNA expression and activity in the liver, pancreas, and subcutaneous—but not visceral—fat. The increase in 11β-HSD1 occurred before animals developed obesity or overt features of the metabolic syndrome. In contrast to rodents, in utero dexamethasone exposure did not alter glucocorticoid receptor expression in metabolic tissues in marmosets.

CONCLUSIONS

These data suggest that long-term upregulation of 11β-HSD1 in metabolically active tissues may follow prenatal “stress” hormone exposure and indicates a novel mechanism for fetal origins of adult obesity and the metabolic syndrome.The metabolic syndrome and its component features (central obesity, insulin resistance/type 2 diabetes, hypertension, dyslipidemia) have been causally linked to early life events as marked by low birth weight and other features of an adverse intrauterine environment (1,2). Two major etiological hypotheses of the “developmental origins” effects have been proposed: malnutrition and glucocorticoid overexposure (3,4). These mechanisms of “programming” may be linked because maternal undernutrition increases maternal glucocorticoid concentrations and reduces the placental enzymatic barrier to maternal glucocorticoids in rats, thus increasing fetal glucocorticoid exposure (5). Moreover, maternal glucocorticoid administration reduces food intake in rodents (6).The processes that link intrauterine insults and later risk of the metabolic syndrome are not yet understood. The metabolic syndrome resembles the rare Cushing''s syndrome of circulating glucocorticoid excess, but in uncomplicated metabolic syndrome, plasma cortisol levels are not raised, spawning the suggestion that increased tissue sensitivity to glucocorticoid action may be important in its pathogenesis (7). In the major metabolic organs, tissue sensitivity and exposure to glucocorticoids are determined by the density of intracellular glucocorticoid receptors and the activity of the microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyzes the regeneration of active cortisol (corticosterone in rodents) from inert cortisone (11-dehydrocorticosterone) (7). 11β-HSD1 is highly expressed in liver and adipose tissue, where glucocorticoids reduce insulin sensitivity and action (7).In obese humans and in monogenic obesity in rodents, there is a selective increase in 11β-HSD1 mRNA and activity in adipose tissues (8–10). Increased 11β-HSD1 in liver is found in other causes of metabolic syndrome, such as myotonic dystrophy (11). Transgenic overexpression of 11β-HSD1 selectively in adipose tissue in mice recapitulates all the major features of metabolic syndrome without changes in circulating steroid levels (12), whereas overexpression of 11β-HSD1 in liver alone produces an attenuated syndrome with insulin resistance, dyslipidemia, and hypertension, but not hyperglycemia or obesity (13). Conversely, 11β-HSD1 knockout mice are insulin sensitized and resist metabolic syndrome with dietary obesity (14).However, genetic variation in the HSD1B1 gene does not associate with obesity (15), suggesting the cause of increased 11β-HSD1 in adipose tissue in obesity is environmentally determined. Although many factors may upregulate 11β-HSD1 in the short term, attempts to chronically induce 11β-HSD1 in adipose tissue by nongenetic approaches have been unsuccessful. In particular, high-fat diets in rodents downregulate 11β-HSD1 in adipose tissue (16), although this does not appear to occur in humans (17), underlining the importance of relevant models of the human situation.Here, we have explored the early life antecedents of metabolic syndrome and especially 11β-HSD1 expression in metabolic tissues in a nonhuman primate model (the common marmoset monkey) of fetal programming.     

Laparoscopic Roux-en-Y Gastric Bypass in Morbidly Obese Patients ≥55 Years Old

Background Advanced age is considered a relative contraindication to bariatric surgery at some institutions because of concerns about higher morbidity and less than optimal weight loss. The aim of our study was to evaluate the operative outcomes, length of stay, weight loss, and improvement of comorbidities in patients ≥55 years old who underwent laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery in our institution. Methods Retrospective data on 33 patients (26 women and 7 men) ≥55 years of age who underwent LRYGB from January 2003 to December 2006 were reviewed. Results Average patient age was 59 years (range 55–68 years), and the mean preoperative body mass index was 47 kg/m² (range 41.1–55.8 kg/m²). The median length of hospital stay was 3 days. There were no intraoperative or postoperative deaths. Early complications were one anastomotic leak, two upper gastrointestinal bleedings, and two readmissions for intractable vomiting. Late complications included four anastomotic strictures and one small bowel obstruction. Patients were followed for a mean 13 months (range 3–24 months). The mean excess body weight (EBW) loss was 13.5 kg (23%), 23.3 kg (39.8%), 33.3 kg (58.1%), 39.8 kg (66.8%), 40.1 kg (69.5%), and 40.8 kg (75.3%) at 1, 3, 6, 9, 12 and 24 months, respectively. Diabetes mellitus improved in 19 (100%) patients and completely resolved in 10 (53%). Hypertension improved in 18 (64%) patients, completely resolved in 9 (32%) and was unchanged in 10 (36%). Conclusions LRYGB is safe and effective in morbidly obese patients ≥55 years of age.     

Are there Predictive Factors of Severe Liver Fibrosis in Morbidly Obese Patients with Non-alcoholic Steatohepatitis?

Background: Non-alcoholic steatohepatitis (NASH) is a clinicopathological entity characterized by the presence of steatosis and lobular and/or portal inflammation with or without fibrosis. Patients with non-alcoholic fatty liver and fibrosis on liver biopsy have increased liver-related deaths. Methods: 181 wedge liver biopsies, taken at the time of bariatric surgery from patients with a mean body mass index (BMI) of 47, were studied. In all cases, the liver biopsy was performed without knowledge of the patient's clinical and biochemical data, which were then examined with univariate and multivariate analysis. Results: Diagnosis of NASH was established in 105 patients (91%); 74 patients (70%) showed mild steatosis, 20 (19%) had moderate inflammation and fibrosis, and 11 (10%) had steatosis with severe fibrosis. None of the liver biopsies showed cirrhosis. Age was the only independent predictor of moderate and severe fibrosis (p=0.001). Conclusions: Since only age was a predictor of moderate or severe fibrosis, and no clinical or biochemical abnormalities detected slowly progressive hepatic fibrosis, liver biopsy is the only means of detecting progression to more advanced liver disease in a NASH patient.     

Can 11β-Hydroxysteroid Dehydrogenase Activity Predict the Sensitivity of Bone to Therapeutic Glucocorticoids in Inflammatory Bowel Disease?

In healthy individuals measures of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme activity predict the change in bone formation markers in response to therapeutic glucocorticoids. It is unclear whether these measures remain predictive in inflammatory disease. We therefore examined whether 11β-HSD1 activity predicts changes in bone markers and bone mineral density (BMD) in patients with inflammatory bowel disease (IBD) treated with therapeutic glucocorticoids. Prospective and cross-sectional studies were carried out in patients attending a gastroenterology clinic with active (n = 39) or clinically inactive (n = 34) IBD and healthy controls (n = 51). Urinary corticosteroid metabolite profiles were obtained on a spot urine sample and total corticosteroid metabolite excretion and 11β-HSD1 activity (measured as the ratio of tetrahydrocortisol to tetrahydrocortisone metabolites, [THF+alloTHF]/THE) determined. Patients with active disease were treated with an 8-week reducing course of oral prednisolone. The (THF+alloTHF)/THE ratio was significantly increased in patients with IBD, even those in clinical remission. The baseline (THF+alloTHF)/THE ratio failed to predict the decrease in bone formation markers or hip BMD. Measures of 11β-HSD activity do not predict bone loss during glucocorticoid treatment of active IBD, probably due to disease-related increases in 11β-HSD1 activity. Our observation of elevated 11β-HSD1 activity in clinically inactive IBD implicates gastrointestinal glucocorticoid activation in the maintenance of disease remission.     

Are Morbidly Obese Patients Equally Benefitting From Care Improvements in Total Hip Arthroplasty?

BackgroundMorbidly obese patients have increased rates of complications following primary total hip arthroplasty (THA) and it is not clear whether improvements in THA care pathways are equally benefitting these patients. The purpose of this study is to assess if reductions in complications have similarly improved for both morbidly obese and non-morbidly obese patients after THA.MethodsPatients undergoing primary THA between 2011 and 2019 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Patients were stratified by body mass index (BMI) <40 and ≥40 kg/m². Thirty-day rates of infectious complications, readmissions, reoperation, and any complication were assessed. Trends in complications were compared utilizing odds ratios and multivariate analyses.ResultsIn total, 234,334 patients underwent THA and 16,979 (7.8%) had BMI ≥40 kg/m². Patients with BMI ≥40 kg/m² were at significantly higher odds for readmission, reoperation, and infectious complications. Odds for any complication were lower for morbidly obese patients in 2011, not different from 2012 to 2014, and higher from 2015 to 2019 compared to lower BMI patients. Odds for any non-transfusion complication were higher for morbidly obese patients and there was no improvement for either group over the study period. There were improvements in rates of readmission and reoperation for patients with BMI <40 kg/m² and readmission for BMI >40 kg/m².ConclusionOdds for readmission and reoperation for non-morbidly obese patients and readmission for morbidly obese patients improved from 2011 to 2019. Reductions in transfusions are largely responsible for improvements in overall complication rates. Although morbidly obese patients remain at higher risk for complications, there does not appear to be a growing disparity in outcomes between morbidly obese and non-morbidly obese patients.     

Is it More Difficult to Cannulate the Right Internal Jugular Vein in Morbidly Obese Patients than in Nonobese Patients?

BACKGROUND: The placement of an internal jugular vein (IJV) catheter is considered to be more difficult in morbidly obese patients. The objective of this study was to compare the success of simulated IJV puncture between morbidly obese patients and a nonobese control group. METHODS: Thirty-four morbidly obese patients with body mass index (BMI, kg/m(2)) >/=40 were compared with 36 patients with BMI < 30. Right IJV puncture was simulated using an ultrasound probe directed towards the sternal notch at the midpoint between the sternal notch and the mastoid process. The investigator placing the probe was blinded as to the image being created on the ultrasound machine. Success rate was assessed at three different head rotation angles from midline; 0 degrees , 30 degrees , and 60 degrees . RESULTS: There was no statistically significant difference in successful simulated IJV puncture between two groups for any of the head positions. However, there was a higher incidence of the carotid artery (CA) puncture in the morbidly obese patient group when the head rotation was advanced from neutral position to 60 degrees (p < 0.05). In addition, the ultrasound showed significantly more overlapping of the IJV over the CA in morbidly obese patients at 0 degrees (p < 0.05) and 30 degrees (p < 0.05). Our results show no statistically significant difference in success rate of IJV puncture between morbidly obese patients and nonobese patients. Keeping the head in a neutral position in morbidly obese patients minimizes the overlapping of the IJV over the CA and the risk of CA puncture. CONCLUSION: However, due to the fact that even in the neutral position there is a significant increase in overlap between IJV and CA, we recommend the use of ultrasound guidance for IJV cannulation in obese patients.     

ProSeal™ LMA Increases Safe Apnea Period in Morbidly Obese Patients Undergoing Surgery under General Anesthesia

Background

Morbidly obese patients are at risk of hypoxemia at the time of induction of anesthesia. The aim of this study was to assess the possible increase in the safe apnea time with the use of ProSeal laryngeal mask airway (PLMA) as a conduit prior to laryngoscope-guided intubation in morbidly obese patients undergoing surgery under general anesthesia.

Methods

Hundred patients with BMI greater than 35 kg/m², undergoing surgery under general anesthesia, were randomly divided to receive either PLMA or facemask with oropharyngeal airway (FM) as the airway device. Following preoxygenation with 100 % oxygen with continuous positive airway pressure of 10 cm H₂O, in ramp position for 5 min the patients were made apneic. From start of apnea to the time to reach SpO2 to 92 % was recorded as safe apnea time. Ventilation was initiated and time to reach SpO2 of 100 % was recorded as recovery time.

Results

The mean safe apnea time was 205 (96–320)?s in FM vs. 337 (176–456) s in PLMA (P?=?0.0000). The mean recovery period was 49 (36–68)?s in FM vs. 42(30–56)?s in PLMA groups (P?=?0.0000). Arterial blood gas analysis showed significant difference in pO2 between the two groups.

Conclusion

The use of ProSeal laryngeal mask airway prior to laryngoscope-guided intubation is beneficial in increasing safe apnea period and achieving faster recovery from hypoxemia in morbidly obese patients.     

Prophylactic Cholecystectomy,a Mandatory Step in Morbidly Obese Patients Undergoing Laparoscopic Roux-en-Y Gastric Bypass?

Background  

The aim of this study was to determine the incidence of symptomatic gallstone disease requiring cholecystectomy (CCE) after laparoscopic Roux-en-Y gastric bypass (LRYGBP) and to identify the peri-operative risk factors associated with postoperative symptomatic gallstone disease.