Alcohol and the effect on some appetite-regulating hormones in man

Beverage containing alcohol has been used for centuries to stimulate appetite. Ingestion of a moderate amount of alcohol increase energy intake. Regulation of food intake is complex. Several factors cooperate such as neural impulses from sensory organs; sight, smell, gut distension, social setting, memory, current energy status and hormones. How alcohol affects these factors is not well understood. This research project has focused on how alcohol influences the peripheral secretion of hormones, known to convey information from the periphery to hunger-regulating centers in the brain about the prevailing caloric homeostasis. Leptin produced by adipocytes - and gut-derived peptide YY (PYY) are two such hormones which inhibit food intake, whereas ghrelin produced by cells in the upper part of the gastro intestinal tract - stimulates appetite. These hormones have central effects on hypothalamic neuropeptide Y (NPY) and on pro-opiomelanocortin (POMC) which stimulates and down-regulates hunger, respectively. Other gut hormones, having central effects as well as influence on intestinal motility, are glucagon-like peptide (GLP-1) and obestatin. Liver derived insulin-like growth factor-1 (IGF-1) and its binding protein insulin-like growth factor binding protein-1 (IGFBP-1) are also of interest in this context, as they are affected by nutritional status and could be factors which influence appetite-regulating centers directly or indirectly via peripherally produced hormones. Aim: To study the effect of alcohol on the secretion of peripheral hormones known to be involved in the regulation of food intake. Material and Methods: 51 healthy subjects (26F/25M) were included in the study. All were young, healthy, normal weight and free of medication. In five separate experiments subjects were investigated in groups of 7 12 individuals. In exp 1, 2 and 3 the effect of alcohol on various hormone levels in serum, was compared with the effect of drinking water. In exp 2 the alcohol effect on urinary excretion of catecholamines was determined with or without oral beta-receptor blockade (propranolol). In exp 5 alcohol influence on gastro-intestinal hormones was investigated with or without sucralfate gastroprotection. Results and discussion: A moderate amount of alcohol induced a significant inhibition of both diurnal and nocturnal secretion of leptin. Factors known to affect the secretion of leptin such as insulin, glucose, cortisol, testosterone, and catecholamines were not influenced by the drug. IGFBP-1 increased significantly after alcohol, contrasting IGF-1, which remained unchanged. This resulted in a low IGF-1/IGFBP-1 ratio and, as a consequence, in a decreased IGF-1 bioavailability. Alcohol had both acute and prolonged inhibitory effect on serum levels of both total and octanoylated ghrelin, but was without significant influence on serum concentrations of NPY, PYY, GLP-1 and obestatin. Gastro-protection with sucralfate did not change the alcohol-induced inhibition of leptin and ghrelin secretion. Conclusion: Acute ingestion of alcohol inhibits the secretion of leptin and ghrelin, induces a marked decline in the IGF-1/IGFBP-1 ratio, but leaves NPY, PYY, GLP-1 and obestatin unchanged. Previous studies suggest that leptin may have long-term rather than acute inhibitory effects on hunger. Therefore, the present findings do not lend strong support to the hypothesis that alcohol has acute stimulatory effect on appetite by influencing peripherally produced hormones. If alcohol has appetite-stimulating properties in humans it is more likely that this is an effect caused by direct influence on appetite-regulating neurons in the brain

Characteristics, Treatment, Outcomes, and Survival in Neuroendocrine G1 and G2 Pancreatic Tumors : Experiences From a Single Tertiary Referral Center

Purpose Neuroendocrine tumors of the pancreas (Pan-NETs) are usually hormonally inactive with a capacity to metastasize. Since Pan-NETs are rare, more knowledge is needed. Methods We reviewed all patients' medical files with Pan-NET treated at a tertiary center (2006-2019). Grade 1 (G1) and grade 2 (G2) tumors were compared. The latter group was subdivided arbitrarily based on proliferation index into G2a (3-9.9%) and G2b (10-19.9%). Results We found 137 patients (76 females, 61 males; G1 n=66, G2 n=42), the median age at diagnosis 61 years (interquartile range (IQR) 50-71), and tumor size 2 cm (1.3-5 cm). The initial surgery was performed in 101 patients. The remaining (n=36) were followed conservatively. Metastatic disease was evident in 22 patients (16%) at diagnosis while new lesions developed in 13 out of 22 patients (59%). In patients without previous metastatic disease, progressive disease was discovered in 29% of G1 vs. 55% of G2 patients (P=0.009), 47% of G2a vs. 75% of G2b patients (NS). Survival was poorer in patients with metastasis at diagnosis vs. those with local disease (P<0.001). During follow-up of 74 months, Pan-NET related death was found in 10 patients. Survival was not different between G1 vs. G2 or G2a vs. G2b, or if tumors were functional. Size <= 2 cm was associated with a better outcome (P=0.004). During the follow-up of small tumors (<= 2 cm, n=36) two were resected. Conclusion In small non-functional Pan-NETs, active surveillance is reasonable. Progressive disease was more common in G2, but survival was similar in G1, G2 and between G2 subgroups. Survival was poorer in patients with metastasis at diagnosis

Liothyronine Use in Hypothyroidism and its Effects on Cancer and Mortality

Background: The prescription of liothyronine (LT3) to treat hypothyroidism is increasing worldwide; however, the long-term safety of LT3 use has yet to be determined. Previous studies have suggested a possible association between LT3 use and breast cancer. The aim of this study was to examine the effects of LT3 use on cancer incidence and mortality. Methods: Our sample included the full adult population of individuals living in Sweden with at least three purchases of thyroid hormone therapy between July 2005 and December 2017. Individual-level data on drug purchases were linked to registry data on cancer incidence and mortality. There were 575,461 individuals with at least three purchases, of which 11,147 had made at least three purchases of LT3, including combinations of levothyroxine (LT4) and LT3. Individuals were followed for a median follow-up time of 8.1 years. We applied Cox regression with a time-varying exposure variable, comparing LT3 users (individuals with at least three cumulative purchases of LT3) with LT4-only users (the rest). Outcomes included breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, and breast cancer mortality. We adjusted for age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose in multivariate analyses. Results: Multivariate analyses produced a hazard ratio of 0.93 (95% confidence interval [0.75-1.15]) for breast cancer incidence (only females), 0.97 (0.87-1.08) for any cancer incidence, 0.69 (0.61-0.77) for all-cause mortality, 0.78 (0.62-0.98) for any cancer mortality, and 0.91 (0.50-1.66) for breast cancer mortality (only females). Conclusions: In this large, Swedish, long-term registry-based study, the use of LT3 did not lead to increased breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality compared with LT4 use. Somewhat surprisingly, there was evidence of lower mortality in LT3 users in models adjusting for dose, potentially an artifact of underlying associations between dose and health status/diagnosis

A Prospective Investigation of Graves' Disease and Selenium: Thyroid Hormones, Auto-Antibodies and Self-Rated Symptoms

BACKGROUND: In Graves' thyrotoxicosis tachycardia, weight loss and mental symptoms are common. Recovery takes time and varies between patients. Treatment with methimazole reduces thyroid hormone levels. According to previous research, this reduction has been faster if selenium (Se) is added. OBJECTIVE: The objective was to investigate whether supplementing the pharmacologic treatment with Se could change the immune mechanisms, hormone levels and/or depression and anxiety. METHODS: We prospectively investigated 38 patients with initially untreated thyrotoxicosis by measuring the thyroid-stimulating hormone (TSH), free thyroxine (FT(4)), free triiodothyronine (FT(3)), thyroid receptor antibodies and thyroid peroxidase auto-antibodies before medication and at 6, 18 and 36 weeks after commencing treatment with methimazole and levo-thyroxine, with a randomized blinded oral administration of 200 µg Se/day or placebo. The selenoprotein P concentration was determined in plasma at inclusion and after 36 weeks. The patients were also assessed with questionnaires about depression, anxiety and self-rated symptoms before medication was started and after 36 weeks. RESULTS: FT(4) decreased more in the Se group at 18 weeks (14 vs. 17 pmol/l compared to the placebo group, p = 0.01) and also at 36 weeks (15 vs. 18 pmol/l, p = 0.01). The TSH increased more in the Se group at 18 weeks (0.05 vs. 0.02 mIU/l, p = 0.04). The depression and anxiety scores were similar in both groups. In the Se group, the depression rates correlated negatively with FT(3) and positively with TSH. This was not seen in the placebo group. CONCLUSIONS: Se supplementation can enhance biochemical restoration of hyperthyroidism, but whether this could shorten clinical symptoms of thyrotoxicosis and reduce mental symptoms must be investigated further

Pheochromocytomas and Abdominal Paragangliomas: A Practical Guidance

Pheochromocytomas and abdominal paragangliomas (PPGLs) are rare tumors arising from the adrenal medulla or the sympathetic nervous system. This review presents a practical guidance for clinicians dealing with PPGLs. The incidence of PPGLs has risen. Most cases are detected via imaging and less present with symptoms of catecholamine excess. Most PPGLs secrete catecholamines, with diffuse symptoms. Diagnosis is made by imaging and tests of catecholamines. Localized disease can be cured by surgery. PPGLs are the most heritable of all human tumors, and germline variants are found in approximately 30–50% of cases. Such variants can give information regarding the risk of developing recurrence or metastases as well as the risk of developing other tumors and may identify relatives at risk for disease. All PPGLs harbor malignant potential, and current histological and immunohistochemical algorithms can aid in the identification of indolent vs. aggressive tumors. While most patients with metastatic PPGL have slowly progressive disease, a proportion of patients present with an aggressive course, highlighting the need for more effective therapies in these cases. We conclude that PPGLs are rare but increasing in incidence and management should be guided by a multidisciplinary team

Highly proliferative anal neuroendocrine carcinoma : molecular and clinical features of a rare, recurrent case in complete remission

Background Poorly differentiated anal neuroendocrine carcinomas (ANECs) are rare lesions with poor prognosis, and the molecular etiology is only partially understood. Case presentation At our institution, we have treated and followed a patient with such a rare ANEC. He had primarily surgery followed by three rounds of repeated surgery for loco-regional recurrences. He also received three different combinations of chemotherapy and external beam radiation. At last follow-up 13 years since the primary diagnosis, the patient had been in complete remission for nine years. The patient's medical files were re-examined, including laboratory, radiology and clinical examinations. Histopathology was re-assessed, and expanded immunohistochemistry was performed from tissue specimens from the four surgical procedures. In addition, the molecular genetic status was evaluated through next-generation sequencing. The initial tumor was consistent with a 59 mm small cell neuroendocrine cancer with a Ki-67 index of 80%. Regional lymph node metastases were evident, and immunohistochemistry supported a neuroendocrine origin. A PCR screening detected human papilloma virus type 45 DNA (high-risk subtype), and focused next-generation sequencing found a missense mutation in thePhosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha(PIK3CA) gene. In tissues representing subsequent recurrences, the Chromogranin A expression was lost, and the Ki-67 index increased to 90%. Conclusions For the first time, we report the detection of HPV45 in a case of ANEC. To our belief,PIK3CAmutations have also not been previously demonstrated in this tumor entity. In highly malignant ANECs, cure can in rare cases be achieved. Although speculative, expression of HPV45 and/or thePIK3CAmutation may have contributed to the favorable outcome

Riedel Thyroiditis

Abstract Context Riedel thyroiditis (RT) is a rare inflammatory autoimmune disease that is often a clinically diagnostic dilemma because of its insidious presentation and nonspecific symptoms. Objective The aim of the present systematic review and meta-analysis is to clarify the presentation, management, and outcomes of RT. Study Selection A systematic search of PubMed/MEDLINE and Web of Science was conducted to identify relevant reports published up to September 2019. Data Extraction First author, country, patient sex, ethnicity, presentation, biochemical status, duration of symptoms, histology, treatment, follow-up duration, and short- and long-term outcomes. Data Synthesis Data from 212 RT patients were retrieved. The mean age was 47 years with a predominantly female population (81%). Neck swelling (89%), dyspnea (50%), and neck pain (41%) were the most common presenting symptoms. Inflammatory markers were elevated in 70% to 97% and thyroid antibody positivity was present in less than 50%. Up to 82% underwent surgical intervention, with the most common being total thyroidectomy in 34% of individuals. Glucocorticoids were used in 70% of individuals with median duration 3 months. Prognosis was reasonable with 90% having resolution or improvement of symptoms. Conclusions This analysis is the largest and most comprehensive to date of RT and provides clinicians with vital information on the common presentation features that may alert to the diagnosis and highlight management options

Limited Genetic Overlap Between Overt Hashimoto's Thyroiditis and Graves' Disease in Twins : A Population-based Study

Context: Hashimoto's thyroiditis (HT) and Graves' disease (GD) are known to coaggregate in families, but the magnitude and nature of a shared etiology is unknown. Objectives: To estimate the shared genetic influence on overt HT and GD and to examine if the heritability differs between men and women. Design, setting, and patients: We used national health registries to identify cases of HT and GD in a cohort of 110 814 Swedish twins. By comparing intra-class and cross-twin cross-trait correlations in dizygotic and monozygotic twins, we calculated heritability and the proportions thereof shared between the diseases. Univariate estimates of heritability were calculated by sex. Results: The heritability for HT and GD was 65% (95% CI, 61-70) and 63% (95% CI, 55-72), respectively. The genetic correlation was 0.35 (95% CI, 0.20-0.50) and shared genetic effects accounted for 8% of the variance for both HT and GD. Univariate heritability was significantly higher in men than in women for HT (90% vs 60%, P < 0.001) but not for GD (79% vs 63%, P = 0.085). Conclusions: From a genetic perspective, HT and GD appear to be only modestly related diseases. Hence, the term "autoimmune thyroid disease," used to cluster these disorders, may have limited validity in a genetic context. Moreover, the mechanisms contributing to HT are partly different for the sexes, with genetic components more important in men