Fotios Kalfarentzos

Improved Levothyroxine Pharmacokinetics After Bariatric Surgery

BACKGROUND The absorption of levothyroxine (LT4) is affected by many factors. Bariatric surgery is recommended in severely obese patients. The aim of this study was to determine the consequences of bariatric surgery on LT4 pharmacokinetic parameters, and to identify the regions of the gastrointestinal tract where LT4 is absorbed in patients with severe obesity before and after surgery. METHODS We studied 32 severely obese nonhypothyroid patients who underwent sleeve gastrectomy (SG; n=10), Roux-en-Y gastric bypass (RYGBP; n=7), or biliopancreatic diversion with long limbs (BPD-LL; n=15). Before surgery, from 8:00 a.m., blood samples were collected before and every 30 minutes after the oral administration of a solution of 600 μg of LT4. The same procedure was repeated 35 days after surgery. We estimated the pharmacokinetic parameters of LT4 before and after surgery, including the area under the curve (AUC), the peak thyroxine concentration (Cmax), and the time to peak thyroxine concentration (Tmax). RESULTS Following surgery, in the SG group, the mean AUC was higher than it was before surgery (18.97±6.01 vs. 25.048±6.47 [μg/dL]·h; p<0.01), whereas the values of Cmax and Tmax were similar to those before surgery. In the RYGBP group, mean AUC, Cmax, and Tmax were similar before and after surgery. In the BPD-LL group, mean AUC and Cmax were higher after surgery than before (14.18±5.64 vs. 25.51±9.1 [μg/dL]·h, p<0.001; 5.62±1.34 vs. 8.16±2.57 μg/dL, p<0.001, respectively), whereas Tmax was similar. CONCLUSIONS The pharmacokinetic parameters of LT4 absorption are improved following SG and BPD-LL types of bariatric procedures. We conclude that the stomach, the duodenum, and the upper part of the jejunum are not sites for LT4 absorption, because in the above-mentioned bariatric procedures these are bypassed or removed.

Effects of bariatric surgery on HDL structure and functionality: results from a prospective trial

BACKGROUND In addition to high-density lipoprotein cholesterol (HDL-C) levels, HDL quality appears also very important for atheroprotection. Obese patients with metabolic syndrome have significantly reduced HDL-C levels and are usually at increased risk for coronary heart disease. Despite that weight loss benefits these patients, its effects on HDL quality and functionality is currently poorly studied. OBJECTIVES We investigated how rapid weight loss affects HDL structure and its antioxidant potential in patients undergoing a malabsorptive bariatric procedure. METHODS Fasting plasma samples were collected the day before and 6 months after the bariatric procedure from 20 morbidly obese patients with body mass index >50, then HDL was isolated and analyzed by biochemical techniques. RESULTS We report a dramatic alteration in the apolipoprotein ratio of HDL that was accompanied by the presence of more mature HDL subspecies and a concomitant increase in the antioxidant potential of HDL. Interestingly, our obese cohort could be distinguished into 2 subgroups. In 35% of patients (n = 7), HDL before surgery had barely detectable apolipoprotein (apo) A-I and apoCIII, and the vast majority of their HDL cholesterol was packed in apoE-containing HDL particles. In the remaining 65% of patients (n = 13), HDL before surgery contained high levels of apoA-I and apoCIII, in addition to apoE. In both subgroups, surgical weight loss resulted in a switch from apoE to apoA-I-containing HDL. CONCLUSIONS Rapid weight loss exerts a significant improvement in HDL structure and functionality that may contribute to the documented beneficial effect of malabsorptive bariatric procedures on cardiovascular health.

Cortisol in tissue and systemic level as a contributing factor to the development of metabolic syndrome in severely obese patients

CONTEXT Adrenal and extra-adrenal cortisol production may be involved in the development of metabolic syndrome (MetS). OBJECTIVE To investigate the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the expression of HSD11B1, nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptors) α (NR3C1α) and β (NR3C1β) in the liver, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of severely obese patients with and without MetS. METHODS The study included 37 severely obese patients (BMI ≥ 40 kg/m(2)), 19 with MetS (MetS+ group) and 18 without (MetS- group), studied before and during bariatric surgery. Before the day of surgery, urinary free cortisol (UFC) and diurnal variation of serum and salivary cortisol were estimated. During surgery, biopsies of the liver, VAT and SAT were obtained. The expression of HSD11B1, NR3C1α and NR3C1β was evaluated by RT-PCR. RESULTS UFC and area under the curve for 24-h profiles of serum and salivary cortisol were lower in the MetS- group. In the MetS- group, mRNA levels of HSD11B1 in liver exhibited a negative correlation with liver NR3C1α (LNR3C1α) and VAT expression of HSD11B1 was lower than the MetS+ group. CONCLUSIONS We observed a downregulation of the NR3C1α expression and lower VAT mRNA levels of HSD11B1 in the MetS- group, indicating a lower selective tissue cortisol production and action that could protect these patients from the metabolic consequences of obesity. In the MetS- group, a lower activity of the HPA axis was also detected. Taken together, cortisol in tissue and systematic level might play a role in the development of MetS in severely obese patients.

Impaired Pharmacokinetics of Levothyroxine in Severely Obese Volunteers

BACKGROUND Suppressive or replacement doses of levothyroxine (LT4) are affected by the rate and extent of the active ingredient absorbed, as well as by the lean body mass. Obesity has reached epidemic proportions worldwide and is related with many comorbidities. The aim of this study was to determine the pharmacokinetic parameters of LT4 in severely obese individuals and compared them with similar data in lean control subjects. METHODS We studied 62 euthyroid subjects who had negative tests for anti-thyroid peroxidise antibodies (Ab-TPO). Thirty eight of these subjects were severely obese but otherwise healthy (severe obese subjects [SOS] group). Twenty-four were healthy control subjects (control group), with a body mass index of 23.3 ± 1.7 kg/m(2). Subjects received 600 μg oral sodium LT4 after an overnight fast. Serum triiodothyronine (T3), T4, and thyroid-stimulating hormone were measured at baseline. Serum T4 and T3 was measured 0.5, 1, 1.5, 2, 2.5, 3, and 4 hours after LT4 administration. RESULTS Baseline serum T4 and thyroid-stimulating hormone concentrations were higher in the SOS group than in the control group; serum T3 was similar in the two groups. The corrected area under the curve and the maximum T4 concentration after LT4 administration were lower, whereas the time to maximum concentration from the baseline was higher in SOS than in the control group. The estimated plasma volume was higher in the SOS than in the control group. Mean serum T3 levels increased gradually during the four hours after LT4 administration in the control group. In contrast, they decreased gradually in the SOS group. CONCLUSIONS Severely obese individuals may need higher LT4 suppressive or replacement doses than normal-weight individuals due, among other factors, to impaired LT4 pharmacokinetic parameters. The latter could be attributed to their higher plasma volume and/or to delayed gastrointestinal LT4 absorption. T4 conversion to T3 might be defective in severe obesity.

Inter-tissue expression patterns of the key metabolic biomarker PGC-1α in severely obese individuals: Implication in obesity-induced disease

OBJECTIVE PGC-1α is already known as a significant regulator of mitochondrial biogenesis, oxidative phosphorylation and fatty acid metabolism. Our study focuses on the role of PGC1α in morbid obesity, in five different tissues, collected from 50 severely obese patients during planned bariatric surgery. METHODS The investigated tissues included subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscle (SM), extramyocellular adipose tissue (EMAT) and liver. PGC1α expression was investigated with immunohistochemistry and evaluated with microscopy. RESULTS Our findings highlighted significant positive inter-tissue correlations regarding PGC-1α expression between several tissue pairs (VAT-SAT, VAT-SM, VAT-EMAT, SAT-SM, SAT-EMAT, SM-EMAT). Moreover, we found significant negative correlations between PGC1α expression in VAT with CD68 expression in skeletal muscle and EMAT, implying a possible protective role of PGC1α against obesity-induced inflammation. CONCLUSION Unmasking the inter-tissue communication networks regarding PGC-1α expression in morbid obesity, will give more insight into its significant role in obesity-induced diseases. PGC1α could potentially represent a future preventive and therapeutic target against obesity-induced disease, probably through enhancing mitochondrial biogenesis and metabolism.