Pharmacological Management of Obesity: A Century of Expert Opinions in Cecil Textbook of Medicine.

BACKGROUND: Innovations in drug therapy for obesity have had a limited impact on the body mass index, prevalence of medical complications, quality of life, and work potential of a substantial majority of affected persons. STUDY QUESTION: What are the milestones of the changes in the expert approach to the pharmacological management of obesity in the past century? STUDY DESIGN: To determine the changes in the experts' approach to the management of obesity, as presented in a widely used textbook in the United States. DATA SOURCES: The primary sources were chapters describing the management of obesity in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020. Secondary sources were publications retrieved from Medline that clarified technical issues related to the development, regulatory approval, and use of the drugs mentioned in the Cecil Textbook of Medicine. RESULTS: Pharmacological interventions aimed at increasing caloric expenditures through thermogenesis were recommended from 1927 through 1943. Thyroid extracts were prescribed even in the absence of demonstrated hypothyroidism or decreased basal metabolic rate throughout this period. Dinitrophenol was mentioned in 1937, but was banned soon thereafter. Appetite suppression with amphetamine was considered useful from 1943 through 1988, after which the drug was replaced with other centrally acting molecules, such as fenfluramine in 1988, sibutramine in 2000, and rimonabant in 2008, which were in turn withdrawn because of major adverse effects. In the past decade, obesity has been treated with the appetite suppressants phentermine-topiramate, bupropion-naltrexone, lorcaserin, and liraglutide, and with orlistat, a drug promoting fat malabsorption. The change in weight produced by these drugs is generally modest and transient. CONCLUSIONS: The pharmacological management of obesity has remained frustratingly inefficient. The reasons for the relative lack of success may reside in the ever-growing access to dense, palatable, and relatively inexpensive food, coupled with the decrease in energy expenditure created by a sedentary lifestyle.

Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets.

Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis (ATS) are worldwide known diseases with increased incidence and prevalence. These two are driven and are interconnected by multiple oxidative and metabolic functions such as lipotoxicity. A gamut of evidence suggests that sphingolipids (SL), such as ceramides, account for much of the tissue damage. Although in humans they are proving to be accurate biomarkers of adverse cardiovascular disease outcomes and NAFLD progression, in rodents, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of metabolic driven diseases such as diabetes, ATS, and hepatic steatosis. In this narrative review, we discuss the pathways which generate the ceramide synthesis, the potential use of circulating ceramides as novel biomarkers in the development and progression of ATS and related diseases, and their potential use as therapeutic targets in NAFDL-ATS development which can further provide new clues in this field.

Adult-onset Still's disease and the role of dermatological manifestations: A case report and literature review.

Adult-onset Still's disease (AOSD) is a rare inflammatory systemic disease with unknown etiology, characterized by spiking fever, evanescent rash, arthralgia and arthritis, leukocytosis and possible multi-organ involvement. Based on a case report of a 19-year-old man who was admitted to hospital for an influenza-like syndrome associated with a transient and recurrent pale-red disseminated non-specific rash, we performed a PubMed database search for cases and reviews of Adult's Onset Still's Disease published in English in the last 5 years. Due to its heterogeneous clinical manifestations, of which skin rash is an important sign, and the lack of a specific laboratory test, the diagnosis requires the exclusion of a wide range of mimicking disorders and the use of specific scoring systems. The high ferritin levels, major leukocytosis with neutrophilia, absence of typical antibodies for other systemic autoimmune diseases and other markers of infectious disease were the milestones that led to the positive diagnosis. The first line of treatment remains corticosteroid therapy in association with disease-modifying anti-rheumatic drugs.

Role of Gut Microbiota on Onset and Progression of Microvascular Complications of Type 2 Diabetes (T2DM).

Type 2 diabetes mellitus (T2DM) remains one of the most problematic and economic consumer disorders worldwide, with growing prevalence and incidence. Over the last years, substantial research has highlighted the intricate relationship among gut microbiota, dysbiosis and metabolic syndromes development. Changes in the gut microbiome composition lead to an imbalanced gastrointestinal habitat which promotes abnormal production of metabolites, inflammatory status, glucose metabolism alteration and even insulin resistance (IR). Short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), lipopolysaccharide, aromatic amino acids and their affiliated metabolites, contribute to T2DM via different metabolic and immunologic pathways. In this narrative review, we discuss the immunopathogenic mechanism behind gut dysbiosis, T2DM development and the major known diabetic microvascular complications (retinopathy, neuropathy and nephropathy), the beneficial use of pre- and pro-biotics and fecal microbiota transplantation in T2DM management and new findings and future perspectives in this field.

The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD).

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) remain as one of the most global problematic metabolic diseases with rapidly increasing prevalence and incidence. Epidemiological studies noted that T2DM patients have by two-fold increase to develop NAFLD, and vice versa. This complex and intricate association is supported and mediated by insulin resistance (IR). In this review, we discuss the NAFLD immunopathogenesis, connection with IR and T2DM, the role of screening and noninvasive tools, and mostly the impact of the current antidiabetic drugs on steatosis liver and new potential therapeutic targets.

The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity.

Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.

Left Ventricular Diastolic Dysfunction in Type 2 Diabetes-Progress and Perspectives.

In-depth understanding of early cardiovascular manifestations in diabetes is high on international research and prevention agendas given that cardiovascular events are the leading cause of death for diabetic patients. Our aim was to review recent developments in the echocardiographic assessment of left ventricular diastolic dysfunction (LVDD) as a telltale pre-clinical disturbance preceding diabetic cardiomyopathy. We analyzed papers in which patients had been comprehensively assessed echocardiographically according to the latest LVDD guidelines (2016), and those affording comparisons with previous, widely used recommendations (2009). We found that the updated algorithm for LVDD is more effective in predicting adverse cardiovascular events in patients with established LVDD, and less specific in grading other patients (labelled "indeterminate"). This may prove instrumental for recruiting "indeterminate" LVDD cases among patients with type 2 diabetes mellitus (T2DM) in future screening programs. As an interesting consideration, the elevated values of the index E/e' can point to early diastolic impairment, foretelling diabetic cardiomyopathy. Identifying subclinical signs early makes clinical sense, but the complex nature of T2DM calls for further research. Specifically, longitudinal studies on rigorously selected cohorts of diabetic patients are needed to better understand and predict the subtle, slow onset of cardiac manifestations with T2DM as a complicating backdrop.

Pathological aspects underlying pancreatogenous hyperinsulinemic hypoglycemia--report of three cases.

Pancreatogenous hyperinsulinemic hypoglycemia (PHH) is a rare disorder determined by an abnormally high secretion of insulin in the pancreas, in the absence of other medical or pharmacological factors. Either ß-cell tumors (insulinomas) or ß-cell hyperplasia (nesidioblastosis) can determine this pathology. Most publications on insulinomas or nesidioblastosis approached these subjects from a clinical point of view. This paper aims to analyze pathological aspects underlying pancreatogenous hyperinsulinemic hypoglycemia. We present two cases of insulinomas with unusual pancreatic localization and size, one of them showing amyloid deposits in the stroma. In both cases, immunohistochemistry confirmed the clinical and imagistic supposition. The third reported case refers to a 57-year-old patient with nesidioblastosis with isolated disposition of endocrine cells and areas of focal organization, both morphological aspects being extremely rare in adults. Although clinical and laboratory data are usually identical in the two forms of PHH, histopathological and immunohistochemical diagnosis is essential in differentiating insulinomas from nesidioblastosis, as the surgical management is different: enucleation for insulinomas and total or subtotal pancreatectomy for nesidioblastosis.

Insulin resistance and adipokine levels correlate with early atherosclerosis - a study in prediabetic patients.

Cardiovascular risk of prediabetes is still subject to controversies. We analyzed the associations between insulin resistance, adipokines and incipient atherosclerosis estimated by intima-media thickness (IMT) in a cross-sectional study on 122 prediabetic subjects without clinical signs of atherosclerotic disease. Homeostasis model assessment of insulin resistance (HOMA-IR, calculated as fasting insulin × fasting plasma glucose / 22.5), adiponectin, leptin, leptin-to-adiponectin ratio, carotid and femoral IMT were evaluated. We also assessed other parameters related to insulin resistance and adipokines (HbA1c, anthropometric and lipid parameters), as they may also influence atherosclerosis. Carotid IMT was correlated to adiponectin and leptin-to-adiponectin ratio (all p < 0.05), but not with HOMA-IR or leptin, while femoral IMT showed no relationship with these factors. After adjusting for leptin, leptin-to-adiponectin ratio, triglycerides, HDL-cholesterol, cholesterol-to-HDL ratio, triglycerides-to-HDL ratio and HbA1c, IMT values became correlated with HOMA-IR. Adjustment for HOMA-IR induced the appearance of new correlations between adipokines and both IMT values. In conclusion, insulin resistance and adipokines seem related to IMT in prediabetic subjects without clinical signs of arterial obstruction.

Rare types of diabetes mellitus.

Diabetes mellitus is a heterogenous disorder characterized by chronic hyperglycemia and induced by a large number of etiopathogenic conditions. Beside type 1 and type 2 diabetes, which account for almost 90% of all cases, practitioners may encounter patients with more infrequent forms of diabetes, as those induced by mutations of a single gene, atypical immune disorders or neonatal diabetes. Monogenic diabetes is represented by genetic disorders in the structure of the beta-cell (the MODY syndromes and the mutations of mitochondrial DNA) or in the insulin's action (type A insulin resistance syndrome, Rabson-Mendenhall syndrome, leprechaunism, lipodystrophies). The rare forms of immune diabetes are determined by antibodies against insulin or insulin receptor or appear as a component of the "stiff man syndrome". Neonatal diabetes is induced by mutations in genes that control beta-cell development and function and may have a transient or permanent nature. Knowledge of the uncommon forms of diabetes mellitus enables physicians to apply the optimal treatment, to estimate the evolution of the patient and to apply a complete family screening in order to diagnose all other blood relatives as soon as possible.

[Liver cirrhosis--procoagulant stasis]. / Ciroza hepatica--stare procoagulanta?

Abnormal hemostasis tests and bleeding are often associated in liver cirrhosis. In these patients the balance between hypo- and hypercoagulation status is more fragile than in healthy people. In the hemostatic abnormalities associated with chronic liver disease are two main chategory factors: favoring hemorrage and favoring thrombosis. The main factors that favoring hemorrage are: low platelet count, impaired platelet function, decreased levels coagulation factors (II, V, VII, IX, X, XI), quantitative and qualitative abnormalities of fibrinogen, vitamin K defiency, low levels of trombin activable fibrinolisis inhibitor, activat plasminogenic tisular. The factors favoring thrombosis are elevated levels of factors VIII and von Willebrand, decreased levels of protein C, protein S, antithrombin, decreased levels of plasminogen. Traditionally it was thought that arterial and venous thrombosis is rare events in cirrhotic patients but recent studies have indicated that thrombotic complications can paradoxically occur even if clinically an increased risk of hemorrhage is considered. Treatment of venous thrombosis in patients with cirrhosis using routine anticoagulation with heparin and vitamin K antagonists has been described but with a high level of bleeding complications. So, based on the limited data available, AASLD guidelines stated no recommendations for or against the use of anticoagulation in cirrhotic patients with portal thrombosis. Although abnormal hemostasis tests and bleeding are often associated in patients with chronic liver disease it is a relatively poor correlation between hemorrhagic risk and routine diagnostic tests of hemostasis. Management of bleeding complications in liver cirrhosis varies and no general guidelines are available. The main therapeutic strategies are: red cell concentrate, plasma, platelet concentrate, recombinant factor VIIa, factor concentrates, desmopressin, antifibrynolitic agents, thrombopoietin receptor agonists, antibiotics. Clinical studies examining safety and efficacy of the various products for the different bleedeing or trombotic complications of liver cirrhosis need to be initiaded.

[Chronic hepatitis C, steatosis and insulin resistance--clinical implications]. / Hepatita cronica cu virus C, steatoza si insulinorezistenta--implicatii clinice.

Chronic infection with hepatitis C virus is nowadays responsible for many cases of liver disease. According to recent research, it seems to be characterized by a great deal of metabolic abnormalities, most of them due to insulin resistance, which is present in the virus C-induced disease more often than in chronic hepatitis B or in the general population. As insulin resistance significantly impairs the natural course of the viral disease by reducing the efficacy of antiviral treatment and aggravating the development of fibrosis, it becomes more and more plausible that therapeutic intervention aiming to reduce it might contribute to a better course in many patients. Hepatic steatosis is also a frequent feature of chronic hepatitis C, being either induced by the infection with genotype 3 or by a predisposing metabolic background. The relation between steatosis and viral disease prognosis is controversial, probably due to the various factors inducing lipid accumulation. A better understanding of the metabolic substrate of chronic hepatitis C would help developing new approaches in its diagnosis and therapy, hopefully providing a better future to many patients.

[Cardiomyopathy in liver cirrhosis--an undiagnosed entity?]. / Cardiomiopatia--complicatie subevaluata în ciroza hepatica?

Cirrhotic cardiomyopathy is a condition recently known in liver cirrhosis consisting of systolic dysfunction to stress factors, diastolic dysfunction and electrophysiological abnormalities in the absence of cardiac disease. The prevalence of cirrhotic cardiomyopathy remains unknown until now. It can be diagnosed by using a combination of electrocardiograph, 2-dimensional echocardiography, and various serum markers (brain natriuretic factor--BNP, proBNP, TnI). Pathogenic mechanisms underlying cirrhotic cardiomyopathy development include abnormal signaling betaadrenergic, cardiomyocites membrane fluidity changes, interstitial fibrosis, myocardial hypertrophy, altered transmembrane ion channels as intervention with negative inotropic effect of different substances whose concentration is increased in cirrhosis. Major stresses on the cardiovasculary system such as liver transplantations, infections, insertion of transjugular portosystemic stent-shunt (TIPSS) have been demonstrated to put in evidence the presence of cirrhotic cardiomyopathy. Heart failure is a significant cause of mortality after liver transplantation but the improvement of liver function determines cardiac abnormalities reversal. Current management recommendations include empirical, nonspecific and mainly supportive measures, no specific treatment can be recommended, and cardiac failure should be treated as in non-cirrhotic patients with sodium restriction, diuretics, and oxygen therapy when necessary. The exact prognosis remains unclear. The extent of cirrhotic cardiomyopathy generally correlates to the degree of liver insufficiency. Reversibility is possible (either pharmacological or after liver transplantation), but further studies are needed.

[Pharmacologic therapy in peripheral diabetic polyneuropathy]. / Tratamentul medicamentos al polineuropatiei diabetice periferice.

Neuropathy is one of the many complications of diabetes mellitus, along with micro- and macroangiopathy. Chronic sensorimotor distal symmetric polyneuropathy is the most common form between neuropathies; more than 30% of the diabetic patients are affected by this complication. Treatment is based on three cornerstones: (1) multifactorial intervention aimed at normoglycemia; (2) drugs that target pathogenic mechanisms and (3) symptomatic treatment. Among pathogenic treatments, alpha-lipoic acid and benfotiamine are available in several countries. Neuropathic pain, which affects 8-26% of diabetic patients, exerts a substantial impact on the quality of life. Among the centrally acting analgesic drugs, tricyclic antidepressants, carbamazepine, gabapentin and opioids have been mainly used to treat neuropathic pain. More recently, significant pain relief has been reported using agents such as duloxetine, a dual selective serotonin noradrenaline reuptake inhibitor, and pregabalin, an anticonvulsant, a specific modulator of the alpha2delta subunit of the voltage-dependent calcium channels. Until now, at least 50 new molecular entities have reached clinical stage of development. Strategies that may show promise over existing treatments include topical therapies, analgesic combinations and, in future, gene-related therapies.

[Adipocytokines and nonalcoholic steatohepatitis]. / Adipocitokinele si steatohepatita nonalcoolica.

Nonalcoholic steatohepatitis is one of the most common liver diseases. It is part of the nonalcoholic fatty liver disease, which ranges from simple hepatic steatosis to necroinflammation and fibrosis of various degrees, so that many patients can evolve towards advanced liver disfunction and even cirrhosis. Insulin resistance is the main factor involved in the development of fatty liver. As the adipose tissue is the source of many metabolically active peptides (the adipocitokines), their involvement in the pathogenesis of the hepatic steatosis and steatohepatitis began to be intensively studied during the last years. The most substantial information collected until now concerns the tumor necrosis factor alpha (a proinflammatory cytokine that induces insulin resistance, fat accumulation in the liver and even fibrosis and necrosis), adiponectin (an anti-inflammatory adipokine that acts as an insulin sensitizer and a hepatic protector) and leptin (a signal from the adipose tissue mass with effects on the appetite and food intake, but also acting upon insulin secretion and action and perhaps upon the liver fat accumulation).

[Alcoholic ketoacidosis]. / Cetoacidoza alcoolica.

Alcoholic ketoacidosis is an acute metabolic acidosis that typically occurs in people who chronically abuse alcohol and have a recent history of binge drinking, little or no food intake and persistent vomiting. Alcoholic ketoacidosis is a result of starvation with glycogen depletion and counter-regulatory hormone production, a raised nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide (NAD+) ratio related to the metabolism of ethanol, and volume depletion resulting in ketogenesis. Alcoholic ketoacidosis is characterized by elevated serum ketone levels and a high anion gap. Once the diagnosis of alcoholic ketoacidosis is made, the mainstay of treatment is hydration with 5% dextrose in normal saline. With timely and aggressive intervention, the prognosis for a patient with alcoholic ketoacidosis is good.

[Adipocitokines and nonalcoholic steatohepatitis]. / Adipocitokinele si steatohepatita nonalcoolica.

Nonalcoholic steatohepatitis is one of the most common liver diseases. It is part of the nonalcoholic fatty liver disease, which ranges from simple hepatic steatosis to necroinflammation and fibrosis of various degrees, so that many patients can evolve towards advanced liver disfunction and even cirrhosis. Insulin resistance is the main factor involved in the development of fatty liver. As the adipose tissue is the source of many metabolically active peptides (the adipocitokines), their involvement in the pathogenesis of the hepatic steatosis and steatohepatitis has begun to be intensively studied during the last years. The most substantial information collected until now concerns the tumor necrosis factor alpha (a proinflammatory cytokine that induces insulin resistance, fat accumulation in the liver and even fibrosis and necrosis), adiponectin (an anti-inflammatory adipokine that acts as an insulin sensitizer and a hepatic protector) and leptin (a signal of the adipose tissue mass with effects on the appetite and food intake, but also acting upon insulin secretion and action and perhaps upon the liver fat accumulation).

[Specific elements of diagnosis in diabetic nephropathy]. / Elemente specifice de diagnostic paraclinic al nefropatiei diabetice.

Diabetic nephropathy became nowadays the main cause of end-stage renal disease in the Western world. Common diagnosis tools can detect only late stages of the renal disease, without means of reversibility. The scientific research identified some specific methods of evaluation, detecting early modifications in the renal structure and function. These methods are the subject of the present paper.