Emerging Pharmacotherapies for Obesity: A Systematic Review.

The history of anti-obesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the conviction that excess body weight signifies a lack of willpower. However, categories of emerging pharmacotherapies generate hope to reduce obesity rates. This systematic review of phase 2 and phase 3 trials in adults with overweight/obesity investigates the effect of novel weight loss pharmacotherapies, compared to placebo/control or Food and Drug Administration-approved weight loss medication, through searching Medline, Embase, and ClinicalTrials.gov (2012-2024). We identified 53 phase 3 and phase 2 trials, with 36 emerging anti-obesity drugs or combinations thereof and four withdrawn or terminated trials. Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide, survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate. Completed phase 2 trials on incretin-based therapies showed a mean percent weight loss of 7.4-24.2%. Almost half of the drugs undergoing phase 2 trials were incretin analogs. The obesity drug pipeline is expanding rapidly, with the most promising results reported with incretin analogs. Data on mortality and obesity-related complications, such as cardio-renal-metabolic events, are needed. Moreover, long-term follow-up data on the safety and efficacy of weight maintenance with novel obesity pharmacotherapies, along with studies focused on under-represented populations, cost-effectiveness assessments, and drug availability, are needed to bridge the care gap for patients with obesity. Significance Statement Obesity is the epidemic of the 21st century. Except for the newer injectable medications, drugs with suboptimal efficacy have been available in the clinician's armamentarium. However, emerging alternatives of novel agents and combinations populate the obesity therapeutic pipeline. This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives.

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.

Longitudinal proteomics of leptin treatment in humans with acute and chronic energy deficiency-induced hypoleptinemia reveal novel, mainly immune-related, pleiotropic effects.

BACKGROUND: Leptin is known for its metabolic, immunomodulatory and neuroendocrine properties, but the full spectrum of molecules downstream of leptin and relevant underlying mechanisms remain to be fully clarified. Our objective was to identify proteins and pathways influenced by leptin through untargeted proteomics in two clinical trials involving leptin administration in lean individuals. METHODS: We performed untargeted liquid chromatography-tandem mass spectrometry serum proteomics across two studies a) Short-term randomized controlled crossover study of lean male and female humans undergoing a 72-h fast with concurrent administration of either placebo or high-dose leptin; b) Long-term (36-week) randomized controlled trial of leptin replacement therapy in human females with acquired relative energy deficiency and hypoleptinemia. We explored longitudinal proteomic changes and run adjusted mixed models followed by post-hoc tests. We further attempted to identify ontological pathways modulated during each experimental condition and/or comparison, through integrated qualitative pathway and enrichment analyses. We also explored dynamic longitudinal relationships between the circulating proteome with clinical and hormonal outcomes. RESULTS: 289 and 357 unique proteins were identified per each respective study. Short-term leptin administration during fasting markedly upregulated several proinflammatory molecules, notably C-reactive protein (CRP) and cluster of differentiation (CD) 14, and downregulated lecithin cholesterol acyltransferase and several immunoglobulin variable chains, in contrast with placebo, which produced minimal changes. Quantitative pathway enrichment further indicated an upregulation of the acute phase response and downregulation of immunoglobulin- and B cell-mediated immunity by leptin. These changes were independent of participants' biological sex. In the long term study, leptin likewise robustly and persistently upregulated proteins of the acute phase response, and downregulated immunoglobulin-mediated immunity. Leptin also significantly and differentially affected a wide array of proteins related to immune function, defense response, coagulation, and inflammation compared with placebo. These changes were more notable at the 24-week visit, coinciding with the highest measured levels of serum leptin. We further identified distinct co-regulated clusters of proteins and clinical features during leptin administration indicating robust longitudinal correlations between the regulation of immunoglobulins, immune-related molecules, serpins (including cortisol and thyroxine-binding globulins), lipid transport molecules and growth factors, in contrast with placebo, which did not produce similar associations. CONCLUSIONS: These high-throughput longitudinal results provide unique functional insights into leptin physiology, and pave the way for affinity-based proteomic analyses measuring several thousands of molecules, that will confirm these data and may fully delineate underlying mechanisms.

Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans.

Mitochondrial-secreted growth differentiation factor-15 (GDF-15) promotes weight loss in animals. Its effects in humans remain unclear, due to limited research and potential measurement interference from the H202D-variant. Our post-hoc analysis investigates total (irrespective of genetic variants) and H-specific GDF-15 (detected only in H202D-variant absence) in humans under acute and chronic energy deprivation, examining GDF-15 interaction with leptin (energy homeostasis regulator) and GDF-15 biologic activity modulation by the H202D-variant. Total and H-specific GDF-15 increased with acute starvation, and total GDF-15 increased with chronic energy deprivation, compared with healthy subjects and regardless of leptin repletion. Baseline GDF-15 positively correlated with triglyceride-rich particles and lipoproteins. During acute metabolic stress, GDF-15 associations with metabolites/lipids appeared to differ in subjects with the H202D-variant. Our findings suggest GDF-15 increases with energy deprivation in humans, questioning its proposed weight loss and suggesting its function as a mitokine, reflecting or mediating metabolic stress response.

Apolipoprotein C-III in association with metabolic-dysfunction associated steatotic liver disease: A large, multicenter study.

BACKGROUND & AIMS: The available literature on the effect of apolipoprotein C-III (ApoC-III) inhibition in MASLD reveals inconsistencies. The aim of the present work was to examine levels of ApoC-III in the entire spectrum of metabolic-dysfunction associated steatotic liver disease (MASLD). METHODS: This is a multicenter study involving patients enrolled in two gastroenterology-hepatology clinics (Greece and Australia) and in a bariatric-metabolic surgery clinic (Italy), with liver biopsy before and after bariatric surgery or lifestyle modification. RESULTS: Comparing simple MASL to steatohepatitis (MASH) with fibrosis stage F ≥ 2 (at-risk MASH), revealed a marginally significant trend for decreased ApoC-III levels in the latter group (p = 0.07). Multi-adjusted analysis revealed an inverse association between ApoC-III and at-risk MASH (Odds Ratioper 1 mg/dL increase in ApoC-III = 0.91, 95 % Confidence Interval (0.83, 0.99)). ApoC-III interacted with triglycerides in predicting at-risk MASH (p-for-interaction = 0.002). Participants with ApoC-III > median (∼3.75 mg/dL) and normal triglycerides (triglyceridese≤150 mg/dL) had the lowest likelihood to present at-risk MASH (31.8 %) in contrast with participants with ApoC-III < median and hypertriglyceridemia among whom at-risk MASH was recorded in 57.1 %. In multi-adjusted analysis participants with normal triglycerides and high ApoC-III had 64 % lower odds of at-risk MASH compared with their counterparts with ApoC-III < median (OR = 0.36, 95%CI (0.14, 0.86)). Among participants with hypertriglyceridemia, those with ApoC-III < median had less prevalent at-risk MASH compared with those with ApoC-III ≥ median (OR = 0.54, 95%CI (0.32, 0.98)); however in all cases significance was lost when liver enzymes were taken into account. CONCLUSIONS: In advanced disease stages, ApoC-III levels seem to be decreased and advanced organ damage may be a potential explanation. Mendelian randomization studies are needed to confirm or refute this hypothesis.

Relative Energy Deficiency in Sport (REDs): Endocrine Manifestations, Pathophysiology and Treatments.

Research on lean, energy-deficient athletic and military cohorts has broadened the concept of the Female Athlete Triad into the Relative Energy Deficiency in Sport (REDs) syndrome. REDs represents a spectrum of abnormalities induced by low energy availability (LEA), which serves as the underlying cause of all symptoms described within the REDs concept, affecting exercising populations of either biological sex. Both short- and long-term LEA, in conjunction with other moderating factors, may produce a multitude of maladaptive changes that impair various physiological systems and adversely affect health, well-being, and sport performance. Consequently, the comprehensive definition of REDs encompasses a broad spectrum of physiological sequelae and adverse clinical outcomes related to LEA, such as neuroendocrine, bone, immune, and hematological effects, ultimately resulting in compromised health and performance. In this review, we discuss the pathophysiology of REDs and associated disorders. We briefly examine current treatment recommendations for REDs, primarily focusing on nonpharmacological, behavioral, and lifestyle modifications that target its underlying cause-energy deficit. We also discuss treatment approaches aimed at managing symptoms, such as menstrual dysfunction and bone stress injuries, and explore potential novel treatments that target the underlying physiology, emphasizing the roles of leptin and the activin-follistatin-inhibin axis, the roles of which remain to be fully elucidated, in the pathophysiology and management of REDs. In the near future, novel therapies leveraging our emerging understanding of molecules and physiological axes underlying energy availability or lack thereof may restore LEA-related abnormalities, thus preventing and/or treating REDs-related health complications, such as stress fractures, and improving performance.

Precision Medicine in Fatty Liver Disease/Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, and is related to fatal and non-fatal liver, metabolic, and cardiovascular complications. Its non-invasive diagnosis and effective treatment remain an unmet clinical need. NAFLD is a heterogeneous disease that is most commonly present in the context of metabolic syndrome and obesity, but not uncommonly, may also be present without metabolic abnormalities and in subjects with normal body mass index. Therefore, a more specific pathophysiology-based subcategorization of fatty liver disease (FLD) is needed to better understand, diagnose, and treat patients with FLD. A precision medicine approach for FLD is expected to improve patient care, decrease long-term disease outcomes, and develop better-targeted, more effective treatments. We present herein a precision medicine approach for FLD based on our recently proposed subcategorization, which includes the metabolic-associated FLD (MAFLD) (i.e., obesity-associated FLD (OAFLD), sarcopenia-associated FLD (SAFLD, and lipodystrophy-associated FLD (LAFLD)), genetics-associated FLD (GAFLD), FLD of multiple/unknown causes (XAFLD), and combined causes of FLD (CAFLD) as well as advanced stage fibrotic FLD (FAFLD) and end-stage FLD (ESFLD) subcategories. These and other related advances, as a whole, are expected to enable not only improved patient care, quality of life, and long-term disease outcomes, but also a considerable reduction in healthcare system costs associated with FLD, along with more options for better-targeted, more effective treatments in the near future.

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.

Congenital hyperreninemic hypoaldosteronism: A case report.

Congenital hypoaldosteronism is a rare autosomal recessive or dominant endocrinopathy with variable penetrance, secondary to primary defects in aldosterone synthesis that could lead to hypovolemia, hyponatremia, hyperkalemia, failure to thrive, microcephaly, seizures, neurodevelopmental delay, or hearing loss. We present the case of a Colombian patient with congenital hypoaldosteronism, who owns two variants in the CPY11B2 gene, and a heterozygous pathogenic variant for nonclassical congenital adrenal hyperplasia. However, the patient missed follow-up and treatment for 6 years. At the age of 7 years, he resumed medical follow-up with laboratory findings of hyperreninemia and hypoaldosteronism, as well as clinical findings of strabismus, left mixed hyperacusis, and pathological short stature (-4.3 SD). Therefore, a trial of fludrocortisone therapy was started with subsequent improvement in renin levels, weight gain, and growth velocity. After 10 months of the start of the medication, he presented hypertension. There is no literature about the late treatment of this condition for pathological short stature.

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.

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.

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.

Time to transition from a negative nomenclature describing what NAFLD is not, to a novel, pathophysiology-based, umbrella classification of fatty liver disease (FLD).

Non-alcoholic fatty liver disease (NAFLD) is a definition of a prevalent condition that has been given a name describing what the disease is not, mainly due to gaps in the physiopathological understanding of NAFLD when the name was given to it. NAFLD still remains an unmet clinical need to a large extent due to the heterogenicity of the disease and the lack of a more accurate physiology-based classification. In essence, fatty liver disease (FLD) has a multifactorial etiology, including metabolic abnormalities, environmental influences, genetic disorders, and/or their overlap which makes it difficult to diagnose, design appropriate trials for it and treat this disease. Therefore, we propose herein that as our knowledge about this disease continues to grow exponentially, it is time to consider ending this unspecific, negative and broad classification of NAFLD, and turn it into a positive and targeted one describing what the disease is and not what it is not. Thus, we propose the novel FLD "Mantzoros classification". This innovative classification proposes to classify the heterogeneous causes of FLD under one umbrella and eventually lead to a better nomenclature and classification system reflecting pathophysiology. This in turn could lead to both better clinical trials and more personalized care. An additional aim is to generate a dialogue among the experts in this field to eventually reach the right nomenclature for an appropriate disease classification that would facilitate our understanding, approach, diagnosis, and management of this epidemic of FLD. Overall, a novel classification, based on phenotypic manifestations, leading risk factors and probable causes of FLD, could help our understanding and clinically would be accurately defining and differentiating the disease, leading to a more accurate design and execution of clinical trials. This would in turn lead to tangible benefits for all patients suffering from FLD through targeted and more effective personalized treatments.

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.

Severe hypertriglyceridemia as a cause of necrotizing pancreatitis in a pediatric patient with familial hyperchylomicronemia syndrome: A case report.

Familial hyperchylomicronemia syndrome is a monogenic autosomal recessive disorder that causes severe and refractory hypertriglyceridemia. This uncommon condition is challenging to diagnose and treat and can lead to comorbidities such as acute pancreatitis. Although treatment options are limited in the pediatric population, strict diets and treatments approved for other dyslipidemias may be implemented in familial hyperchylomicronemia syndrome, given the lack of pharmacological interventions available. We report a 14-year-old female presented to the emergency room with abdominal pain suggestive of acute pancreatitis. Biochemical analysis revealed a triglyceride value of 4260 mg/dL. Treatment for triglyceride reduction with a strict CHILD-2 triglyceride-lowering diet, insulin infusion, fibrates, and multiple plasmapheresis were initially insufficient. Primary hypertriglyceridemia was suspected, and genetic testing identified a homozygous pathogenic variant in the lipoprotein lipase gene, diagnosing familial hyperchylomicronemia syndrome. She was discharged with a maximum dose of fibrate, statin, omega-3 fatty acids, and a restrictive diet. At her 1-month and 9-month follow-ups, her triglyceride values were 756 and 495 mg/dL, respectively, without incident complications. Familial hyperchylomicronemia syndrome is an uncommon condition with limited available literature and treatment options, especially in the pediatric population. Acute pancreatitis secondary to severe hypertriglyceridemia is a condition with a high risk of mortality which requires prompt clinical suspicion and treatment.

Circulating total and intact GDF-15 levels are not altered in response to weight loss induced by liraglutide or lorcaserin treatment in humans with obesity.

BACKGROUND: Growth differentiation factor 15 (GDF-15) is a stress-response cytokine proposed to be associated with body weight regulation. AIMS: The primary aim was to investigate changes of circulating intact GDF-15 (wildtype, non-carrier of the rs1058587 polymorphism coding for the H2O2D mutation) and total GDF-15 (measured irrespective of the mutation) in response to liraglutide (GLP-1 receptor agonist) and lorcaserin (5-HT2C receptor agonist), two pharmacologic agents that induce food intake and weight reduction. In addition, we perform exploratory correlations of total and intact GDF-15 with clinical, hormonal and metabolo-lipidomic parameters in humans with obesity. MATERIALS AND METHODS: We utilized two studies: 1) Study 1, a randomized, double-blinded, cross-over trial of liraglutide and placebo administration for 5 weeks in subjects with obesity (n = 20; BMI = 35.6 ± 5.9 kg/m2), in escalating doses starting at 0.6 mg/day on week 1 and increased every week, up to the highest dose of 3.0 mg/day during week 5. b) Study 2, a randomized, double-blinded trial of lorcaserin 10 mg twice daily, or placebo for 12-weeks in humans with obesity (n = 34 BMI = 37.4 ± 6.1 kg/m2). Total and intact GDF-15 levels were measured with novel enzyme-linked immunosorbent assays and the metabolomics and lipidomics analysis was performed with nuclear magnetic resonance spectroscopy. RESULTS: Total and intact GDF-15 were positively correlated with diabetes risk index and trimethylamine N-oxide and negatively with eGFR. Despite significant changes in body weight, total and intact GDF-15 were not altered in response to liraglutide or lorcaserin treatment in subjects with obesity. CONCLUSIONS: Total and intact GDF-15 levels are not altered in response to liraglutide or lorcaserin therapy and are thus not directly involved in the metabolic feedback loop pathways downstream of GLP1 or 5-HT2C receptor agonists. Since neither total nor intact GDF-15 levels were altered in response to weight loss, future studies are needed to elucidate the pathways activated by GDF-15 in humans and its role, if any, in body weight regulation and energy homeostasis.

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.

Pediatric diabetic ketoacidosis as type 1 diabetes debut with concurrent SARS-CoV-2 infection: A case report.

Diabetic ketoacidosis is a life-threatening complication associated with type 1 diabetes (T1D). Recent evidence suggests that SARS-CoV-2 could trigger diabetic ketoacidosis in type 1 diabetes susceptibility and previous insulitis; however, the data on SARS-CoV-2-infected patients with diabetic ketoacidosis as their type 1 diabetes are still limited. We report a 13-year-old Latinamerican male with symptoms and laboratory tests diagnostic of diabetic ketoacidosis and positive SARS-CoV-2 reverse transcription polymerase chain reaction, who required mild COVID-19 care management, fluid resuscitation, and insulin infusion at a regular dose, without further complications after the acute infection. Clinical/biochemical improvement allowed outpatient endocrinology follow-up with insulin therapy and continuous glucose monitoring. To our knowledge, we report the first case of diabetic ketoacidosis as the debut of type 1 diabetes in a Colombian pediatric patient with concurrent SARS-CoV-2 infection. Therefore, this report aims to contribute to the global research on SARS-CoV-2 and diabetic ketoacidosis and discuss the approach to these concomitant pathologies.

Hormonal Contraception and Massive Pulmonary Embolism in a COVID-19 Ambulatory Patient: A Case Report.

Coronavirus 19 disease (COVID-19) presents a highly variable clinical presentation and course, ranging from asymptomatic patients to rapidly progressive, fatal pneumonia. The known heterogeneous outcomes can affect both previously healthy patients and those with significant comorbidities, who develop clinical courses with possibly more multisystemic compromise. Likewise, the development of thrombotic phenomena during the acute course of the disease is associated with complications that worsen patient prognosis. We present a case report of a 45-year-old multiparous patient with a history of overweight and chronic use of oral hormonal contraception with low doses of levonorgestrel and estradiol as the only risk factors favoring the development of thrombotic events. During her outpatient COVID-19 clinical course, she developed massive pulmonary thromboembolism resulting in secondary obstructive shock, which required pharmacological thrombolysis. At discharge, hormonal contraception was considered contraindicated, and the patient was released from our institution with continued oral anticoagulant therapy. COVID-19 infection, contraceptive hormone therapy, and overweight are known risk factors for the development of thromboembolic events. The impact of their concomitance has not been studied to date. From our experience, we discuss the impact these risk factors have when present together and invite others to report similar cases.