Circulating total and H-specific GDF15 levels are elevated in subjects with MASLD but not in hyperlipidemic but otherwise metabolically healthy subjects with obesity.

BACKGROUND: Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD. METHODS: Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed. RESULTS: In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders. CONCLUSION: Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946.

Thyroid function, adipokines and mitokines in metabolic dysfunction-associated steatohepatitis: A multi-centre biopsy-based observational study.

BACKGROUND AND AIMS: Thyroid axis is currently under investigation as a therapeutic target in metabolic dysfunction-associated steatotic liver disease (MASLD). Thyroid function was examined herein in the full spectrum of disease. METHODS: Subjects were recruited and had liver biopsies in two Gastroenterology-Hepatology Clinics (Greece and Australia) and one Bariatric-Metabolic Surgery Clinic (Italy). The main working sample was n = 677 subjects with MASLD after excluding subjects with abnormal free thyroxine levels. Participants were classified according to thyroid-stimulating hormone (TSH) standard criteria: Subclinical hyperthyroidism (<0.4 uIU/mL); Euthyroidism with relatively low (0.4 to <2.5 uIU/mL); euthyroidism with relatively high (2.5-4.0 uIU/mL); subclinical hypothyroidism (>4 uIU/mL). RESULTS: TSH as a continuous variable was positively associated with significant fibrosis (F ≥ 2), metabolic dysfunction-associated steatohepatitis (MASH) and at-risk MASH. Subclinical hypothyroidism was associated with fibrosis F ≥ 2 (odds ratio [OR] = 3.47, 95% confident interval [CI] [1.50, 8.05], p = .02), MASH (OR = 3.44, 95% CI [1.48, 7.98] p = .001) and at-risk MASH (OR = 3.88, 95% CI [1.76, 8.55], p = .001), before and after controlling for adiposity, central obesity, and insulin resistance. When leptin, adiponectin, or growth differentiation factor-15 were examined as moderators, significance was lost. Sex-specific analysis revealed a strong association between TSH and the presence of significant fibrosis among women, eliminated only when adipokines/mitokines were adjusted for. Restricted cubic spline analysis revealed associations between TSH and liver outcomes (p-values < .01) with inflection points for fibrosis F ≥ 2 being 2.49, for MASH being 2.67 and for at-risk MASH being 6.96. CONCLUSIONS: These observations provide support for studies on the administration of thyroid hormone in MASLD therapeutics for subclinical hypothyroidism and liver-specific thyroid receptor agonists for subjects across the TSH continuum.

Circulating hormones in biopsy-proven steatotic liver disease and steatohepatitis: A Multicenter Observational Study.

BACKGROUND: The role of metabolic/inflammatory hormonal systems in metabolic dysfunction associated steatotic liver disease (MASLD) remains to be fully elucidated. PURPOSE: To report the levels of the novel total and H-specific growth differentiation factor-15 (GDF-15) and other established hormonal systems and to describe hormonal patterns in controls and patients with MASLD and its stages. METHODS: This is a multicenter study from two Gastroenterology-Hepatology Departments (Greece and Australia) and one Bariatric-Metabolic Surgery Department (Italy). Overall, n = 455 serum samples of patients with biopsy-proven MASLD (n = 374) and Controls (n = 81) were recruited. RESULTS: We report for the first time that total and H-specific GDF-15 levels are higher in MASLD, at-risk metabolic dysfunction associated steatohepatitis (MASH), and severe fibrosis than in Controls. In addition, follistatin-like-3 (FSTL-3), free insulin-like growth factor-1 (IGF-1), leptin, and insulin levels were higher in MASLD patients than in Controls, while adiponectin levels were lower in MASLD subjects than in Controls. Activin-A, follistatin (FST), FSTL-3, and insulin levels significantly increased in severe fibrosis compared to no/mild fibrosis, while free IGF-1 decreased. In addition, adiponectin levels were lower in subjects without fibrosis vs. any fibrosis. Moreover, GDF-15 presented a strong positive association for the likelihood of having MASLD and at-risk MASH, while in adjusted analyses, FST and adiponectin showed inverse associations. Two different patterns of at-risk MASH were revealed through unsupervised analysis (total variation explained=54%). The most frequent pattern met in our sample (34.3%) was characterized by higher levels of total and H-specific GDF-15, follistatins, and activins, as well as low adiponectin levels. The second pattern revealed was characterized by high levels of free IGF-1, insulin, and leptin, with low levels of activin-A and adiponectin. Similar patterns were also generated in the case of overall MASLD. CONCLUSIONS: Total and H-specific GDF-15 levels increase as MASLD severity progresses. FSTL-3, free IGF-1, leptin, and insulin are also higher, whereas adiponectin and activin-A levels are lower in the MASLD group than in Controls. Hormonal systems, including GDF-15, may not only be involved in the pathophysiology but could also prove useful for the diagnostic workup of MASLD and its stages and may potentially be of therapeutic value.

Liver biopsy-based validation, confirmation and comparison of the diagnostic performance of established and novel non-invasive steatotic liver disease indexes: Results from a large multi-center study.

BACKGROUND: Non-invasive tools (NIT) for metabolic-dysfunction associated liver disease (MASLD) screening or diagnosis need to be thoroughly validated using liver biopsies. PURPOSE: To externally validate NITs designed to differentiate the presence or absence of liver steatosis as well as more advanced disease stages, to confirm fully validated indexes (n = 7 NITs), to fully validate partially validated indexes (n = 5 NITs), and to validate for the first time one new index (n = 1 NIT). METHODS: This is a multi-center study from two Gastroenterology-Hepatology Departments (Greece and Australia) and one Bariatric-Metabolic Surgery Department (Italy). Overall, n = 455 serum samples of patients with biopsy-proven MASLD (n = 374, including 237 patients with metabolic-dysfunction associated steatohepatitis (MASH)) and Controls (n = 81) were recruited. A complete validation analysis was performed to differentiate the presence of MASLD vs. Controls, MASH vs. metabolic-dysfunction associated steatotic liver (MASL), histological features of MASH, and fibrosis stages. RESULTS: The index of NASH (ION) demonstrated the highest differentiation ability for the presence of MASLD vs. Controls, with the area under the curve (AUC) being 0.894. For specific histological characterization of MASH, no NIT demonstrated adequate performance, while in the case of specific features of MASH, such as hepatocellular ballooning and lobular inflammation, ION demonstrated the best performance with AUC being close to or above 0.850. For fibrosis (F) classification, the highest AUC was reached by the aspartate aminotransferase to platelet ratio index (APRI) being ~0.850 yet only with the potential to differentiate the severe fibrosis stages (F3, F4) vs. mild or moderate fibrosis (F0-2) with an AUC > 0.900 in patients without T2DM. When we excluded patients with morbid obesity, the differentiation ability of APRI was improved, reaching AUC = 0.802 for differentiating the presence of fibrosis F2-4 vs. F0-1. The recommended by current guidelines index FIB-4 seemed to differentiate adequately between severe (i.e., F3-4) and mild or moderate fibrosis (F0-2) with an AUC = 0.820, yet this was not the case when FIB-4 was used to classify patients with fibrosis F2-4 vs. F0-1. Trying to improve the predictive value of all NITs, using Youden's methodology, to optimize the suggested cut-off points did not materially improve the results. CONCLUSIONS: The validation of currently available NITs using biopsy-proven samples provides new evidence for their ability to differentiate between specific disease stages, histological features, and, most importantly, fibrosis grading. The overall performance of the examined NITs needs to be further improved for applications in the clinic.

The first external validation of the Dallas steatosis index in biopsy-proven Non-alcoholic fatty liver Disease: A multicenter study.

AIMS: A new non-invasive tool (NIT) for non-alcoholic fatty liver disease (NAFLD) proposed in 2022 by the multi-ethnic Dallas Heart Study, i.e. the Dallas Steatosis Index (DSI), was validated herein using for the first time the gold standard i.e. liver biopsy-proven NAFLD. METHODS: This is a multicenter study based on samples and data from two Gastroenterology-Hepatology Clinics (Greece and Australia) and one Bariatric-Metabolic Surgery Clinic (Italy). Overall, n = 455 patients with biopsy-proven NAFLD (n = 374) and biopsy-proven controls (n = 81) were recruited. RESULTS: The ability of DSI to correctly classify participants as NAFLD or controls was very good, reaching an Area Under the Curve (AUC) = 0.887. The cut-off point that could best differentiate the presence vs. absence of NAFLD corresponded to DSI = 0.0 (risk threshold: 50% | Sensitivity: 0.88; Positive Predictive Value (PPV): 93.0%; F1-score = 0.91). DSI demonstrated significantly better performance characteristics than other liver steatosis indexes. Decision curve analysis revealed that the benefit of DSI as a marker to indicate the need for invasive liver assessment was confirmed only when higher DSI values, i.e. ≥ 1.4, were used as risk thresholds. DSI performance to differentiate disease progression was inadequate (all AUCs < 0.700). CONCLUSIONS: DSI is more useful for disease screening (NAFLD vs. controls) than to differentiate diseases stages or progression. The value of any inclusion of DSI to guidelines needs to be further studied.

Ectopic parathyroid adenoma causing hyperparathyroidism-induced psychosis: A case report.

Primary hyperparathyroidism is a disease with multisystemic and heterogeneous manifestations, characterized by underlying high parathormone concentrations. Despite neuropsychiatric involvement being one of the manifestations, psychosis is rare. This is the case of a 68-year-old female with a 10-day clinical course of anorexia, mutism, dysphagia, constipation, and weight loss. The patient had disorganized speech associated with paranoid delusions. Prior to this visit, the patient was recently diagnosed with a mixed anxiety-depressive disorder. For this reason, treatment with antidepressants in combination with atypical antipsychotics was administered without a satisfactory response. Neuroimaging, infectious panel, and toxicology screening showed no abnormal findings. Hypercalcemia secondary to a retropharyngeal ectopic parathyroid adenoma was the causative etiology of her primary hyperparathyroidism, and hypercalcemia treatment resolved the psychotic episode. We highlight the importance of recognizing psychosis as a possible initial presentation of hyperparathyroidism and hypercalcemia. Ruling out organic etiologies prior to diagnosing a primary cause of psychosis is crucial, as their treatment can reverse the psychotic symptoms.

Myxedema heart disease and non-comatose presentation of myxedema: A case report.

Myxedema coma is an emergency that develops from non-diagnosed or severe hypothyroidism and requires early recognition and management. Cardiac manifestations are uncommon and pose a challenge in the recognition of myxedema coma. We present the case of a 76-year-old male with a history of thyroidectomy secondary to a follicular carcinoma, who presented with dyspnea, generalized edema, drowsiness, disorientation, memory loss, and episodic generalized tonic-clonic seizures. Antiepileptic and diuretic treatment for seizures and heart failure exacerbation did not improve the symptoms. Further blood analysis revealed a thyroid-stimulating hormone and free thyroxine of 163 mUL/L and 0.64 ng/dL, respectively. Treatment with intravenous hydrocortisone and levothyroxine led to progressive clinical improvement. Uncommon clinical manifestations such as cardiac and non-specific neurologic symptoms should be considered as manifestations of myxedema coma. A comatose mental status is not a universal manifestation, and milder symptoms should be considered. An adequate assessment, including diagnostic scores and prompt hormonal supplementation prevents fatal consequences.

Recent guidelines for Non-Alcoholic Fatty Liver disease (NAFLD)/ Fatty Liver Disease (FLD): Are they already outdated and in need of supplementation?

Non-Alcoholic Fatty Liver Disease (NAFLD) is a highly prevalent disease and unmet clinical need that we have recently proposed to be renamed for simplicity and accuracy as Fatty Liver Disease (FLD), with specific subclassifications. It has been commonly associated with metabolic comorbidities, including obesity, type 2 diabetes (T2D), hypertension, and hyperlipidemia. Since no Federal and Drug Administration (FDA) approved treatments exist to date, recent guidelines recommend lifestyle interventions, bariatric surgery, and pharmacotherapy, i.e. glucagon-like peptide-1 receptor agonists (GLP-1RA), peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, and SGLT-2 inhibitors for its treatment. A new and novel medication for the treatment of T2D, tirzepatide, a dual GIP/GLP-1RA, was approved by the FDA only one week after guidelines were published, and ongoing clinical trials demonstrate promising results not only for T2D but also for body weight and steatosis. Moreover, we realize that distinct subgroups exist under the umbrella of FLD and, thus, more precise therapeutic recommendations would be needed towards the goal of personalized medicine and therapeutics for these subgroups. As the metabolism field is moving forward very fast and as several molecules in development will most likely demonstrate benefits in NAFLD treatment in the foreseeable future, guidelines will need to be frequently updated. This rapid pace of change prompts us to propose that guidelines should exist as living online documents on the websites of professional societies, so that they continue being updated following and reflecting the rapid progress in this and other fields of medicine.

Evaluación del conocimiento y práctica de la limitación del esfuerzo terapéutico en personal asistencial de una institución prestadora de servicios de salud para pacientes oncológicos de Medellín, 2018 / Evaluating the Knowledge and Practice of Limitation of Therapeutic Effort in Health Workers at a Health Care Institution for Cancer Patients in Medellín, 2018 / Avaliação do conhecimento e da prática da limitação de esforço terapêutico em equipe de atendimento de uma instituição prestadora de serviços de saúde para pacientes oncológicos de Medellín, 2018

Resumen La limitación del esfuerzo terapéutico (LET) es toda acción que implique suspender o no iniciar tratamientos o medidas terapéuticas en pacientes que no se beneficiarán clínicamente. En Latinoamérica, las investigaciones realizadas dejan en evidencia la falta de familiarización y discordancia que hay alrededor del tema y sus prácticas. El presente estudio buscó objetivizar el conocimiento en LET del personal de salud de una institución de Medellín, a partir de una encuesta autoaplicada que permitió el desarrollo de un estudio descriptivo de tipo transversal, con muestreo no probabilístico. Dentro de los resultados se encontró que el 56,5 % de los encuestados refirió conocer el concepto, y el 90 % manifestó aplicarlo. Sin embargo, había discordancias dentro de los conceptos clave de la definición y el ejercicio.

Abstract Limitation of therapeutic effort (LTE) is any action that involves suspending or not initiating medical treatment or therapeutic measures in patients who will not receive any clinical benefit. In Latin America, some research has proven a lack of familiarization and disagreement with the subject and its practices. The present study tried to objectify the knowledge of LTE of healthcare personnel at an institute in Medellín using a self-administered survey that allowed conducting a cross-sectional descriptive study with non-probabilistic sampling. Within the results, 56.5 % of respondents understood the concept of LTE, and 90 % applied it actively. However, there were discrepancies regarding the core concepts of the definition and practice.

Resumo A limitação de esforço terapêutico (LET) é toda ação que implique suspender ou não iniciar tratamentos ou medidas terapêuticas em pacientes que não se beneficiarão clinicamente. Na América Latina, as pesquisas realizadas evidenciam a falta de familiarização e a discordância que há ao redor do tema e suas práticas. O presente estudo procurou objetivar o conhecimento em LET da equipe de saúde de uma instituição de Medellín, utilizando um questionário auto aplicado que permitiu o desenvolvimento de um estudo descritivo de tipo transversal, com amostragem não probabilística. Dentro dos resultados constatou-se que 56,5 % dos pesquisados disseram conhecer o conceito, e 90 % manifestaram aplicá-lo. No entanto, havia discordâncias dentro dos conceitos chave da definição e da prática.

The Effect of the Economic Crisis on Adolescents' Perceived Health and Risk Behaviors: A Multilevel Analysis.

BACKGROUND: Previous studies have analyzed the impact of economic crises on adult's health and lifestyles, but evidence among children and adolescents is limited. The objective of this study was to analyze the impact of the economic crisis on self-perceived health and some risk behaviors in the Spanish adolescent population. METHODS: We used data from four waves (2002, 2006, 2010, 2014) of the Health Behavior in School-Aged Children (HBSC) survey in Spain. Separate multilevel logistic and linear regression models were applied for health complaints, self-rated health, life satisfaction, smoking, alcohol consumption, and breakfast skipping. Annual change in Spanish regional unemployment rates was used as a proxy of the economic crisis. An increasing set of control variables were included, consisting of individual, socioeconomic, and family and peer relationships indicators. Median odds ratios were estimated to quantify the cross-region and cross-school variation. RESULTS: Increases in unemployment rates were linked to a higher risk of poorer health and bad habits in the simplest models. The effect was no longer statistically significant when indicators of family and peer relationships were included, suggesting a protective effect against the impact of the economic crisis. Our findings also show that schools had a larger effect on health and lifestyles than regions. CONCLUSION: The child's social context-family, peers, school, and region-play an important role on the effects of the economic crisis on health and risk behaviors.

Risk Factors for Treatment Failure and Mortality Among Hospitalized Patients With Complicated Urinary Tract Infection: A Multicenter Retrospective Cohort Study (RESCUING Study Group).

Background: Complicated urinary tract infections (cUTIs) are responsible for a major share of all antibiotic consumption in hospitals. We aim to describe risk factors for treatment failure and mortality among patients with cUTIs. Methods: A multinational, multicentre retrospective cohort study, conducted in 20 countries in Europe and the Middle East. Data were collected from patients' files on hospitalised patients with a diagnosis of cUTI during 2013-2014. Primary outcome was treatment failure, secondary outcomes included 30 days all-cause mortality,among other outcomes. Multivariable analysis using a logistic model and the hospital as a random variable was performed to identify independent predictors for these outcomes. Results: A total of 981 patients with cUTI were included. Treatment failure was observed in 26.6% (261/981), all cause 30-day mortality rate was 8.7% (85/976), most of these in patients with catheter related UTI (CaUTI). Risk factors for treatment failure in multivariable analysis were ICU admission (OR 5.07, 95% CI 3.18-8.07), septic shock (OR 1.92, 95% CI 0.93-3.98), corticosteroid treatment (OR 1.92, 95% CI 1.12-3.54), bedridden (OR 2.11, 95%CI 1.4-3.18), older age (OR 1.02, 95% CI 1.0071.03-), metastatic cancer (OR 2.89, 95% CI 1.46-5.73) and CaUTI (OR 1.48, 95% CI 1.04-2.11). Management variables, such as inappropriate empirical antibiotic treatment or days to starting antibiotics were not associated with treatment failure or 30-day mortality. More patients with pyelonephritis were given appropriate empirical antibiotic therapy than other CaUTI [110/171; 64.3% vs. 116/270; 43%, p <0.005], nevertheless, this afforded no advantage in treatment failure rates nor mortality in these patients. Conclusions: In patients with cUTI we found no benefit of early appropriate empirical treatment on survival rates or other outcomes. Physicians might consider supportive treatment and watchful waiting in stable patients until the causative pathogen is defined.