A. Verónica Araya

Enhancement in liver SREBP-1c/PPAR-α ratio and steatosis in obese patients: Correlations with insulin resistance and n-3 long-chain polyunsaturated fatty acid depletion

Sterol receptor element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) mRNA expression was assessed in liver as signaling mechanisms associated with steatosis in obese patients. Liver SREBP-1c and PPAR-alpha mRNA (RT-PCR), fatty acid synthase (FAS) and carnitine palmitoyltransferase-1a (CPT-1a) mRNA (real-time RT-PCR), and n-3 long-chain polyunsaturated fatty acid (LCPUFA)(GLC) contents, plasma adiponectin levels (RIA), and insulin resistance (IR) evolution (HOMA) were evaluated in 11 obese patients who underwent subtotal gastrectomy with gastro-jejunal anastomosis in Roux-en-Y and 8 non-obese subjects who underwent laparoscopic cholecystectomy (controls). Liver SREBP-1c and FAS mRNA levels were 33% and 70% higher than control values (P<0.05), respectively, whereas those of PPAR-alpha and CPT-1a were 16% and 65% lower (P<0.05), respectively, with a significant 62% enhancement in the SREBP-1c/PPAR-alpha ratio. Liver n-3 LCPUFA levels were 53% lower in obese patients who also showed IR and hipoadiponectinemia over controls (P<0.05). IR negatively correlated with both the hepatic content of n-3 LCPUFA (r=-0.55; P<0.01) and the plasma levels of adiponectin (r=-0.62; P<0.005). Liver SREBP-1c/PPAR-alpha ratio and n-3 LCPUFA showed a negative correlation (r=-0.48; P<0.02) and positive associations with either HOMA (r=0.75; P<0.0001) or serum insulin levels (r=0.69; P<0.001). In conclusion, liver up-regulation of SREBP-1c and down-regulation of PPAR-alpha occur in obese patients, with enhancement in the SREBP-1c/PPAR-alpha ratio associated with n-3 LCPUFA depletion and IR, a condition that may favor lipogenesis over FA oxidation thereby leading to steatosis.

Decreased Liver Fatty Acid Δ-6 and Δ-5 Desaturase Activity in Obese Patients

Steatosis in obese nonalcoholic fatty liver disease (NAFLD) patients is a clinicopathological condition associated with depletion of n‐3 polyunsaturated fatty acids (PUFA), a feature that may be related to PUFA desaturation. Liver Δ‐6 and Δ‐5 desaturase (Δ‐6D and Δ‐5D) activities, homeostasis model assessment of insulin resistance (HOMAIR), and ferric reducing ability of plasma (FRAP) were evaluated in 13 obese patients who underwent subtotal gastrectomy with gastro‐jejunal anastomosis in Roux‐en‐Y and 15 nonobese patients who underwent laparoscopic cholecystectomy (controls). Liver Δ‐6D and Δ‐5D activities in obese patients were 87% and 66% lower than controls (P < 0.001), respectively, with a 62% diminution in the Δ‐6D/Δ‐5D activity ratio (P < 0.02). Δ‐6D inversely correlated with both HOMAIR (r = −0.70, P < 0.0001) and oxidative stress assessed as the reciprocal value of FRAP (r = −0.40, P < 0.05). Δ‐5D negatively correlated with HOMAIR (r = −0.48, P < 0.01) but not with FRAP−1 (r = −0.13, not significant). In conclusion, liver PUFA desaturation is diminished in obese NAFLD patients, in association with underlying insulin resistance and oxidative stress, which may play a role in altering lipid metabolism favoring fatty infiltration.

Liver NF‐κB and AP‐1 DNA Binding in Obese Patients

Oxidative stress and insulin resistance (IR) are major contributors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and in the progression from steatosis to nonalcoholic steatohepatitis (NASH). Our aim was to assess nuclear factor‐κB (NF‐κB) and activating protein‐1 (AP‐1) activation and Toll‐like receptor 4 (TLR4) expression as signaling mechanisms related to liver injury in obese NAFLD patients, and examined potential correlations among them, oxidative stress, and IR. Liver NF‐κB and AP‐1 (electromobility shift assay (EMSA)), TLR4 expression (western blot), ferric reducing ability of plasma (FRAP), and IR evolution (HOMA) were evaluated in 17 obese patients who underwent subtotal gastrectomy with gastro‐jejunal anastomosis in Roux‐en‐Y and 10 nonobese subjects who underwent laparoscopic cholecystectomy (controls). Liver NF‐κB and AP‐1 DNA binding were markedly increased in NASH patients (n = 9; P < 0.05) compared to controls, without significant changes in NAFLD patients with steatosis (n = 8), whereas TLR4 expression was comparable between groups. Hepatic NF‐κB activation was positively correlated with that of AP‐1 (r = 0.79; P < 0.0001); both liver NF‐κB and AP‐1 DNA binding were inversely associated with FRAP (r = −0.43 and r = −0.40, respectively; P < 0.05) and directly correlated with HOMA (r = 0.66 and r = 0.62, respectively, P < 0.001). Data presented show enhanced liver activation of the proinflammatory transcription factors NF‐κB and AP‐1 in obese patients with NASH, parameters that are significantly associated to oxidative stress and IR.

Interleukin-6 production and deregulation of the hypothalamic-pituitary-adrenal axis in patients with major depressive disorders.

The present study was designed to determine whether an association exists between HPA activity and cytokine production in major depression (MD). In 9 patients with MD and 11 control subjects of both sexes, all drug-free, activity of the HPA axis was evaluated by circadian rhythm of plasma cortisol, 24-h free urinary cortisol, an overnight 1 mg dexamethasone suppression test, and an oCRF stimulation test. Spontaneous and LPS-stimulated production of IL-1β, IL-6, and TNFα by peripheral blood mononuclear cells were also determined. We found a significantly elevated spontaneous production of IL-6 in patients with MD (3541.2 ± 726.8 vs 380.4 ± 77.5 pg/mL in controls, p<0.05), while LPS-stimulated production was significantly lower in patients than in control subjects (19,867.7 ± 3649.2 vs 33,142.2 ± 15,47.2 pg/mL, p<0.05). The adrenocorticotropic hormone response to oCRF, evaluated as the area under the curve (AUCACTH) was significantly lower in patients than in control subjects (p=0.02). A positive correlation between AUCACTH and LPS-stimulated IL-6 secretion was observed in patients with MD (r=0.75, p<0.05) but not in controls. These findings suggest that the activation of the inflammatory response described in depression might be associated with long-term hyperactivity of the HPA axis.

Alta frecuencia de anticuerpos anti-tiroperoxidasa (ATPO) positivos en sujetos adultos, sin patología tiroidea conocida, de Santiago de Chile

BACKGROUND Anti-thyroid peroxidase antibodies have a pathogenic role in Hashimoto thyroiditis. Between 10 and 19% of individuals without thyroid disease, have positive titers of these antibodies. AIM To study the frequency of positive titers of anti-thyroid peroxidase antibodies in healthy individuals. MATERIAL AND METHODS A blood sample, to measure anti-thyroid peroxidase antibodies and thyroid stimulating hormone (TSH) by chemoluminiscense assay, was obtained from 67women and 62 men aged 45 +/- 14years, without a personal or familiar history of thyroid diseases and normal thyroid palpation. The cutoff point of the manufacturer to consider positive a titer of anti-thyroid peroxidase antibodies was set at 35 IU/ml. RESULTS Twenty-eight women and 28 men had positive antibody titers (43% of the sample). Subjects in the upper tercile of anti-thyroid peroxidase antibody titers had a higher TSH than those in the second tercile, although within normal limits (1.73 +/- 0.74 and 1.37 +/- 0.59 mlU/L, respectively p = 0.02) CONCLUSIONS: Forty three percent of the studied subjects without personal or familial history of thyroid diseases had positive titers of anti-thyroid peroxidase antibodies. Further prospective studies should evaluate whether this observation discloses an increase in thyroid autoimmune disease in a population with increased iodine intake.

Evaluación por inmunohistoquímica de la expresión de hormonas hipofisiarias y del marcador de proliferación celular Ki-67 en tejido de adenomas causantes de acromegalia

Forty one paraffin embedded surgical samples of pituitary adenomasfrom patients with acromegalia were studied. Immunohistochemistry for GH, prolactin (PRL),follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone(TSH), adrenocorticotropin (ACTH) and for the expression of Ki-67 was carried out.

Disminución de masa ósea post-cirugía bariátrica con by-pass en Y de Roux

INTRODUCTION Bariatric surgery has important metabolic complications such as bone mass loss. GOAL To assess bone mineral density (BMD) after Roux-en-Y gastric by-pass (RYGB) in patients under standard calcium and vitamin D supplementation. METHOD In patients with morbid obesity submitted to RYGB, 76 women and 22 men of diverse age, all with standard nutritional instruction including vitamin D and calcium, we measured BMD with a dual X-ray densitometer. They had lumbar spine and hips measurement 2-3 years post-surgery. Twenty females were followed up with BMD until of a mean of 54 months. Using World Health Organization (WHO) criterias, values were compared with young controls and same age and sex population, evaluating osteopenia and osteoporosis. RESULTS Inverse correlation was observed between BMD and age; positive between BMD and body mass index as well as with preoperative weight excess. In women younger than 45 years, we observed a diminished BMD in 26.8% of them, with no cases of osteoporosis. In older females, BMD was decreased in 65.7% (p = 0.0011); corresponding to 45.7% of osteopenia and 20% osteoporosis, more frequent in lumbar spine. In the females subgroup followed longer, BMD diminished progressively mainly in left hip. In men, there was 36% of osteopenia and 14% of osteoporosis. CONCLUSION Patients from both genders and diverse ages after BPYR presented osteopenia and osteoporosis, despite early supplement prescription of calcium and vitamin D. We consider important to perform serial BMD measurements and also to individualize therapy with risk factors control.Introduction: Bariatric surgery has important metabolic complications such as bone mass loss. Goal: To assess bone mineral density (BMD) after Roux-en-Y gastric by-pass (RYGB) in patients under standard calcium and vitamin D supplementation. Method: In patients with morbid obesity submitted to RYGB, 76 women and 22 men of diverse age, all with standard nutritional instruction including vitamin D and calcium, we measured BMD with a dual X-ray densitometer. They had lumbar spine and hips measurement 2-3 years post-surgery. Twenty females were followed up with BMD until of a mean of 54 months. Using World Health Organization (WHO) criteria’s, values were compared with young controls and same age and sex population, evaluating osteopenia and osteoporosis. Results: Inverse correlation was observed between BMD and age; positive between BMD and body mass index as well as with preoperative weight excess. In women younger than 45 years, we observed a diminished BMD in 26.8% of them, with no cases of osteoporosis. In older females, BMD was decreased in 65.7% (p = 0.0011); corresponding to 45.7% of osteopenia and 20% osteoporosis, more frequent in lumbar spine. In the female’s subgroup followed longer, BMD diminished progressively mainly in left hip. In men, there was 36% of osteopenia and 14% of osteoporosis. Conclusion: Patients from both genders and diverse ages after BPYR presented osteopenia and osteoporosis, despite early supplement prescription of calcium and vitamin D. We consider important to perform serial BMD measurements and also to individualize therapy with risk factors control.

Descripción de los hallazgos en el perfil lipídico y proteico de pacientes dependientes a cocaína, en abstinencia reciente

BACKGROUND Chronic cocaine users develop multiple potentially lethal ischemic vascular complications associated with accelerated atherosclerosis. AIM To assess biochemical and lipid profiles among cocaine dependent subjects in recent abstinence. MATERIAL AND METHODS A blood sample to measure blood count, biochemical and lipid profiles was obtained from 78 patients aged 19 to 53 years (78% males) who complied with DSM-IV criteria for cocaine dependency. Laboratory results were compared with a group of normal subjects. RESULTS All cases had positive urinary cocaine, with a mean consumption lapse of 7.6 years. The frequency of smoking was higher in cases. Dependent males had higher body mass index than controls. Compared to controls, dependent females had significantly higher triglyceride (TG) levels and lower HDL cholesterol. Therefore the relation total/HDL cholesterol was higher (p = 0.0365). Dependent males had higher TG levels than their normal counterparts. Dependent subjects consuming cocaine base-paste had higher TG levels. Total proteins, albumin, urea and blood urea nitrogen were lower in dependent subjects. Among males, serum creatinine was lower and blood urea was positively correlated with the daily amount of cocaine use (p = 0.03). After a month of strict abstinence, lipid profile was repeated in 27 patients and remained unchanged. CONCLUSIONS Chronic cocaine use was associated with higher TG in both genders and lower HDL cholesterol in women when compared with a group of healthy counterparts.Background: Chronic cocaine users develop multiple potentially lethal ischemic vascular complications associated with accelerated atherosclerosis. Aim: To assess biochemical and lipid profiles among cocaine dependent subjects in recent abstinence. Material and methods: A blood sample to measure blood count, biochemical and lipid profiles was obtained from 78 patients aged 19 to 53 years (78% males) who complied with DSM –IV criteria for cocaine dependency. Laboratory results were compared with a group of normal subjects. Results: All cases had positive urinary cocaine, with a mean consumption lapse of 7.6 years. The frequency of smoking was higher in cases. Dependent males had higher body mass index than controls. Compared to controls, dependent females had significantly higher triglyceride (TG) levels and lower HDL cholesterol. Therefore the relation total/HDL cholesterol was higher (p=0.0365). Dependent males had higher TG levels than their normal counterparts. Dependent subjects consuming cocaine base-paste had higher TG levels. Total proteins, albumin, urea and blood urea nitrogen were lower in dependent subjects. Among males, serum creatinine was lower and blood urea was positively correlated with the daily amount of cocaine use (p=0.03). After a month of strict abstinence, lipid profile was repeated in 27 patients and remained unchanged. Conclusions: Chronic cocaine use was associated with higher TG in both genders and lower HDL cholesterol in women when compared which a group of healthy counterparts.

Remisión espontánea de acromegalia y enfermedad de Cushing en adultos mayores. Casos clínicos

Pituitary diseases such as acromegaly and Cushings disease require surgical or medical therapy. In some functioning pituitary tumors, a spontaneous remission of hormonal hypersecretion is observed, mainly associated to apoplexy or pituitary infarction. We report the evolution of two female patients older than 70 years at the time of diagnosis, with multiple comorbidities. In case 1, acromegaly was diagnosed at 74 years of age. Sellar CT scan showed a 10-mm adenoma. During her follow-up, IGF1 levels remained normal. Nine years later, a magnetic resonance (MR) showed a 7-mm adenoma. In case 2, clinical and biochemical diagnosis of Cushings disease was done being 71 years old. Sellar MR showed a 6-mm adenoma. Three years later, urinary cortisol normalized with no changes in adenoma at MR. Seven years later, she remains without clinical or biochemical signs of hypercortisolism. In both cases, no signs of hemorrhage were observed at MR.

Análisis de falsos negativos en la cintigrafía SPECT de paratiroides con sestamibi en pacientes con hiperparatiroidismo primario sometidos a cirugía entre 2008-2015 en hospital universitario

BACKGROUND 99mTc-sestamibi parathyroid SPECT scintigraphy is a useful tool in the pre-operative study of hyperparathyroidism. False negatives (FN) have been reported in 5.7-14% of the examinations. AIM To characterize 99mTc-sestamibi FN in cases referred for primary hyperparathyroidism (PHP) to a university hospital. MATERIAL AND METHODS Descriptive retrospective analysis. We included patients with PHP, studied with SPECT scintigraphy, operated at our center between 2008 and 2015. Clinical and surgical data were recorded; biopsies of the FN were blindly reviewed by one pathologist. RESULTS One hundred twenty one scintigraphies fulfilled the inclusion criteria. Seven (5.8%) were negative and 114 positive. There was no difference in age, sex and PTH levels between FN and true positive scintigraphies. At surgery, one FN case had two hyperplasic glands and two cases had ectopic glands. Pathology reported adenoma in three cases, hyperplasia in three and carcinoma in one. The largest diameter of the lesion was lower in FN (1.3 and 2.1 cm respectively, p = 0.02) and the proportion of adenomas was higher in true positive cases (29% and 75% respectively; p < 0.01). The interval between scintigraphy and parathyroidectomy was greater in FN with a median of 92 days (range 20 days-3.2 years, p < 0.01). The percentage of oxyphilic cells observed was similar in both groups. CONCLUSIONS FN parathyroid SPECT scintigraphies in PHP are uncommon. They corresponded to lesions under the equipments resolution limit and resulted in longer time lags between scintigraphy and surgery.