[Non-alcoholic steatohepatitis (NASH) : a model of metabolic inflammation («metaflammation¼)]. / Stéatohépatite non alcoolique (NASH) : un modèle d'inflammation métabolique («métaflammation¼).

Diseases related to fatty liver, independently of alcohol consumption («non-alcoholic fatty liver disease¼ or NAFLD), are increasing because of the epidemics of obesity and type 2 diabetes. These disorders reflect a continuum that comprises isolated steatosis, steatohepatitis (NASH) and fibrosis, with, at the end, an increased risk of cirrhosis and hepatocarcinoma. It has been recently proposed to replace the term NAFLD by MAFLD, i.e. «Metabolic (dysfunction) Associated Fatty Liver Disease¼, which better reflects the pathogenesis of the disease. Inflammation plays a crucial role in the aggravation of the disorder and profoundly influences the prognostic evolution. This article illustrates the natural history of this underestimated metabolic disorder, recall the diagnostic criteria used in clinical practice, emphasizes the deleterious role of inflammation and discusses some therapeutic perspectives.

: Les maladies liées à un «foie gras¼, indépendamment de la consommation d'alcool («non-alcoholic fatty liver disease¼ ou NAFLD), sont en augmentation en raison de l'«épidémie¼ d'obésité et de diabète de type 2. Il s'agit d'un continuum comprenant la stéatose isolée, la stéatohépatite (NASH) et la fibrose avec, in fine, un risque accru de cirrhose et d'hépatocarcinome. Il a été proposé récemment de remplacer le terme NAFLD par MAFLD pour «Metabolic (dysfunction) Associated Fatty Liver Disease¼, ce qui reflète mieux la pathogénie de la maladie. L'inflammation joue un rôle clé dans l'aggravation du trouble et conditionne l'évolution pronostique. Cet article retrace l'histoire naturelle de cette pathologie métabolique sous-estimée, rappelle les critères diagnostiques utilisés en clinique, précise le rôle délétère de l'inflammation et conclut par quelques perspectives thérapeutiques.

[How to explore...the metabolic syndrome by its new IDF definition]. / Comment j'explore...le syndrome métabolique par sa nouvelle définition dite de "consensus".

The International Diabetes Federation recently proposed a so-called consensus definition of metabolic syndrome. According to this new definition, a subject has the metabolic syndrome if he/she has abdominal obesity (considered as a prerequisite and assessed, in the European population, by a waist circumference > 80 cm in women and > 94 cm in men) and, in addition, at least two other risk factors among 1) elevated fasting triglycerides > or = 150 mg/dl; 2) low HDL cholesterol HDL < 50 mg/dl in women and < 40 mg/dl in men; 3) increased arterial blood pressure > or = 130/ 85 mm Hg; and 4) elevated fasting plasma glucose concentration > or = 100 mg/dl. We will discuss the advantages and limitations of this new definition as well as the consequences of its use on the prevalence of the metabolic syndrome in the Belgian population.

[Role of clinical chemistry in the assessment and follow up of a diabetic patient]. / Apport de la biologie clinique dans la mise au point et le suivi d'un patient diabétique.

Clinical chemistry is essential in the management of a patient with diabetes mellitus. It plays a major role in the diagnosis by measuring plasma glucose levels, in the fasting state or two hours after an oral glucose load. It helps in the definition of the type of diabetes by measuring plasma C-peptide concentration, a marker of residual endogenous insulin secretion, or by detecting islet cell antibodies, a marker of autoimmune disease. Finally, clinical chemistry is essential in assessing the quality of overall blood glucose control thanks to the dosage of glycated haemoglobin (HbA1c) and in demonstrating the adequate control of cardiovascular risk factors associated to the metabolic syndrome, especially dyslipidaemia.

[Bariatric surgery: 10-year results of the Swedish Obese Subjects Study]. / L'étude clinique du mois. Chirurgie bariatrique: les résultats à 10 ans de la "Swedish Obese Subjects Study".

The 10-year results of the prospective, controlled Swedish Obese Subjects Study were recently reported in the New England Journal of Medicine by L. Sjöström and colleagues. This trial compared obese subjects who underwent gastric surgery and contemporaneously matched, conventionally treated obese control subjects. The follow-up rate for laboratory examinations was 74.5 percent at 10 years. At that time, data of 627 patients of the control group (mean age of 48 years, body mass index of 41 kg/m2) were compared to those of 641 patients who were submitted to surgery (banding n = 156, vertical banded gastroplasty n = 451 and gastric bypass n =34). At 10 years, the body weight had increased by 1.6 percent in the control group and decreased by 16.1 percent in the surgery group (p < 0.001), and similar changes were observed for waist circumference (+2.8 percent versus -10.1 percent, respectively, p < 0.001). Energy intake was lower and the proportion of physically active subjects higher in the surgery group than in the control group throughout the observation period. Ten-year rates of recovery from diabetes, hypertriglyceridaemia, low levels of high-density lipoprotein cholesterol, hypertension, and hyperuricaemia were more favourable in the surgery than in the control group. The surgery group had lower 10-year incidence rates of diabetes, hypertriglyceridaemia, and hyperuricaemia (but not of hypertension) than the control group. In conclusion, as compared with conventional therapy, bariatric surgery appears to be a valuable option for the treatment of severe obesity, resulting in long-term weight loss, improved lifestyle, and, except for hypercholesterolaemia that was not significantly affected, amelioration in cardiovascular risk factors that were elevated at baseline. Obtaining long-term data concerning the effect of weight loss on overall mortality and on the incidence rates of myocardial infarction, stroke, and cancer remains a key-objective of this landmark study.

Non-alcoholic steatohepatitis: association with obesity and insulin resistance, and influence of weight loss.

Non-alcoholic steatohepatitis (NASH) is a disease of emerging identity and importance, and is now considered as one of the commonest liver diseases in western countries. It is frequently associated with severe obesity, especially abdominal adiposity, and is intimately related to various clinical and biological markers of the insulin resistance syndrome. Especially, both the prevalence and the severity of liver steatosis are related to male sex, body mass index, waist circumference, hyperinsulinaemia, hypertriglyceridaemia and impaired glucose tolerance or type 2 diabetes. A substantial weight loss following gastroplasty is accompanied by a marked reduction in the prevalence and the severity of the various biological abnormalities of the metabolic syndrome and, concomitantly, by an important regression of liver steatosis in most obese patients. However, in some patients, this rapid and drastic weight loss may result in a mild increase in inflammatory lesions (hepatitis), despite the regression of steatosis, which might result from the rapid mobilization of fatty acids or cytokines from adipose tissue, especially visceral fat. The intimate relationship between NASH and obesity leads to the concept that NASH may be considered as another disease of affluence, as is the insulin resistance syndrome and perhaps being part of it.

Effects of gastroplasty on body weight and related biological abnormalities in morbid obesity.

Obesity is a prevalent metabolic disorder associated with high morbidity and mortality rates. Medical treatment rarely succeeds, and bariatric surgery has been proposed as an alternative therapy. The purpose of this non-controlled retrospective study was to evaluate time-course changes in body weight in severely obese patients who underwent vertical ring gastroplasty or adjustable silicone gastric banding, and to assess the prevalence and potential reversibility of several of the biological abnormalities associated with morbid obesity. From an initial cohort comprising 658 patients, regular body weight measurements and biological data were obtained in 505 patients [419 females, 86 males; age 36 +/- 11 years; body mass index 42.7 +/- 6.9 kg/m2; (mean +/- SD)] with a mean follow-up of 26 +/- 14 months. Mean weight loss was 32 +/- 16 kg. Most weight reduction occurred within the first 6 months, followed by near-stabilisation or even slight weight regain. Most biological parameters were obtained before surgery and after at least 6 months of follow-up. The high prevalence and severity of metabolic disturbances associated with the insulin resistance syndrome (hyperglycaemia, hyperinsulinaemia, decreased HDL cholesterol, hypertriglyceridaemia, elevated fibrinogen levels and hyperuricaemia) before gastroplasty were significantly decreased after weight loss. No major biological deficiencies were observed following gastroplasty, except low iron serum levels. It is concluded that marked weight loss associated with gastroplasty involved a remarkable reduction in the prevalence and severity of several biological abnormalities classically considered as cardiovascular risk factors.

Medical aspects of obesity.

Obesity poses a serious health hazard and its treatment is often disappointing. Major advances have been made during recent years in the understanding of body weight regulation, with the discovery of leptin, a protein produced by adipocytes and acting on the central nervous system to reduce food intake, and that of beta-3 adrenergic receptors and uncoupling proteins which contribute to stimulate energy expenditure. Numerous metabolic complications are associated with abdominal obesity and most of them, such as diabetes mellitus, dyslipidaemias and arterial hypertension, appear to be linked to insulin resistance and may be part of the socalled metabolic syndrome or syndrome X. While very-low-calorie diets are usually effective in the short-term, they cannot, in the long-term and for most patients, solve the problem of severe obesity. Pharmacological antiobesity treatment may include drugs that reduce food intake, drugs that increase energy expenditure and drugs that affect nutrient partitioning or metabolism. All of these pharmacological approaches have potential efficacy, but unfortunately serious limitations. This is also the case of mechanical means, such as intragastric balloons. Consequently, bariatric surgery may be considered as a valuable alternative therapy in well-selected patients with morbid obesity refractory to classical treatments. In conclusion, obesity is a chronic disease and should be treated as such with reasonable expectations.

[How I study anomalies of glucose metabolism, insulin secretion and the insulin sensitivity with an oral glucose tolerance test]. / Comment j'explore ... les anomalies du métabolisme glucidique, de l'insulinosécrétion et de la sensibilité à l'insuline avec une hyperglycémie provoquée par voie orale.

Oral glucose tolerance test (OGTT) has been widely used for the diagnosis of diabetes mellitus, gestational diabetes, impaired glucose tolerance or reactive hypoglycaemia. Simultaneous measurements of plasma glucose and insulin levels also allow to derive indices of insulin secretion and insulin sensitivity. Whereas OGTT is not considered anymore as the first choice for the diagnosis of diabetes mellitus, it remains useful for studying abnormalities of glucose metabolism as well as of insulin secretion and insulin action.

[How I explore ... the controversy concerning the role of oral glucose tolerance test in clinical practice]. / Comment j'explore ... la controverse à propos de la place de l'hyperglycémie provoquée par voie orale en clinique.

The oral glucose tolerance test (OGTT) has been widely used for the diagnosis of diabetes mellitus, gestational diabetes or impaired glucose tolerance. However, since 1997, OGTT is not considered anymore as the first choice test for the diagnosis of diabetes mellitus or impaired glucose tolerance, being replaced by fasting glycaemia. Numerous studies, however, stressed the discrepancies between these two diagnostic approaches, so that OGTT still has defenders as a useful tool to diagnose diabetes. Besides, emphasis has been recently put on both postprandial hyperglycaemia, considered as a major cardiovascular risk factor, and impaired glucose tolerance as a predictor of progression toward overt type 2 diabetes, two parameters well addressed by the OGTT. Thus, even if the place to be reserved to the OGTT is controversial, in our opinion, this test still has a place in clinical biology.

[Metabolic syndrome: definitions and epidemiological data]. / Le syndrome métabolique: définitions et données épidémiologiques.

The metabolic syndrome is strongly related to visceral obesity and associated with a high risk of cardiovascular morbidity and mortality. Since the original description of Reaven in 1988, several working definitions have been proposed, especially by the World Health Organisation in 1998-99, the National Cholesterol Education Program (NCEP-ATP III) Expert Panel in the United States in 2001 and the European Group for the Study of Insulin Resistance (EGIR) in 2002. The present paper attempts at comparing these various definitions and at reporting epidemiological data both in North America and in Europe, especially in Belgium. The prevalence is generally higher in men than in women and strongly increases with age. Overall, one may estimate that around 20% of adults have a metabolic syndrome, which should therefore be considered as an important public health problem.

[How I evaluate ... a overweight or obese patient]. / Comment j'explore ... un sujet avec un excès pondéral ou une obésité.

The evaluation of an obese subject aims at better understanding the disease, its causes and consequences, in order to optimize its management. Schematically, this task can be done in three successive steps. First, it is necessary to analyse data from the past, by asking about family and personal history. Then, the present data should be carefully analysed, especially the severity of overweight, its type of distribution and the importance of associated complications. Finally, it is mandatory to project these data into the future, in order to assess the final prognosis of the obese patient allowing a better definition of the goals and the therapeutical strategies.

[Thyroid disorders and dyslipidemias]. / Dysthyroïdies et dyslipidémies.

While overt thyroid disturbances, characterized by symptoms and/or clinical signs with abnormal serum levels of thyroid hormones, are generally associated with perturbations in the lipid profile, the situation is less clear as far as subclinical thyroid disturbances, defined by isolated abnormalities of thyroid stimulating hormone (TSH) levels, are concerned. In severe hyperthyroidism, a decrease of total cholesterol, LDL cholesterol and apoprotein B concentrations is generally observed. These biological parameters are normalized when appropriate antithyroid treatment is given. In profound hypothyroidism, on the contrary, elevated levels of total and LDL cholesterol levels are observed, which decrease after hormonal replacement. In both cases, the changes in serum levels of HDL cholesterol, triglycerides and lipoprotein (a) are less systematic, both before and after treatment. Lipid abnormalities associated with subclinical thyroid disturbances remain controversial. However, two recent meta-analyses have shown higher LDL cholesterol levels in presence of subclinical hypothyroidism and a significant reduction of such lipid abnormality after administration of thyroxine. Furthermore, they demonstrated a higher prevalence of subclinical hypothyroidism in a population with hypercholesterolaemia when compared to a population with normal cholesterol levels. Finally, a significant reduction in both total and LDL cholesterol concentrations has been reported after administration of thyroxine in a small group of hypercholesterolaemic patients with basal TSH levels in the upper range of normal values. In view of the results of the literature, strategies are proposed to help the clinician in the management of patients with overt or subclinical thyroid disturbances, associated with dyslipidaemia.

[The dosage of anti-GAD and anti-IA2 autoantibodies: an aid to the early diagnosis of type 1 diabetes]. / Le dosage des auto-anticorps anti-GAD et anti-IA 2: une aide au diagnostic précoce du diabète de type 1.

Diabetes mellitus is a frequent metabolic disease characterised by a complex and inconstant phenotypic expression that complicates the classification of patients and sometimes delays their optimal management. In that slowly progressive disease leading to severe and irreversible complications, the use of early and specific genetic, immunological and/or metabolic markers may help in the classification of diabetic patients and in the orientation of therapeutic strategies; furthermore, it is also an essential aid in the early screening of subjects at risk of developing the disease. The assessment of classical immunological markers, such as islet cell antibodies (ICA) or anti-insulin antibodies (IAA) has been recently completed by the screening of new promising markers such as GAD- and IA2-antibodies. The presence of these markers confirms the autoimmune component of the disease and thus supports the diagnosis of type 1 diabetes, even if clinical symptoms are absent or inconsistent. In addition, it represents a strong argument in favour of the initiation of specific immunological therapies to preserve B-cell number and function.

[Obesity and women: esthetic preoccupation or medical problem?]. / L'obésité féminine: souci esthétique ou problème médical?

Women more and more frequently refer to medical doctors for treating weight excess. Even if the primum movens is usually a pure esthetic concern, medical aspects should not be neglected. Indeed, if obesity with gynoid adipose tissue distribution is less deleterious than android obesity from a metabolic point of view, severe obesity is frequently associated with cardiovascular risk factors which may hinder the prognosis of these female patients. Other complications are common in obese women, such as oestrogen-related cancers, osteoarticular problems and psychological disturbances. Various therapeutic approaches are available which permit an encouraging weight loss and a rapid improvement of risk factors. Unfortunately, long-term results are often disappointing, essentially because of the difficulty to follow on the long term a strict diet regimen and practice physical exercise and because of the usual unrealistic expectations of the obese women who consult medical doctors.

[An immunologic etiology for hyperprolactinemia: macroprolactinemia]. / Une étiologie immunologique à l'hyperprolactinémie: la macroprolactinémie.

Besides classical etiologies of hyperprolactinaemia (pregnancy, pharmacological treatments, pituitary or hypothalamic perturbations), another less known cause may explain a spectacular idiopathic elevation of plasma concentrations of prolactin hormone. Macroprolactinaemia is characterized by the presence of a circulating high molecular weight complex of prolactin with an immunoglobulin G. In this article, we report the cases of 3 female patients for whom size exclusion chromatography technique permitted to give a precise biological diagnosis and to avoid heavy, expensive, time consuming and unnecessary clinical investigations or therapeutic actions. Patients with macroprolactinaemia do not exhibit clinical features of classical hyperprolactinaemia, notably as regard to menstrual and fertility disturbances.

[How I treat ... an individual with severe obesity and metabolic abnormalities with gastroplasty]. / Comment je traite ... une obésité sévère et ses anomalies métaboliques par une gastroplastie.

Severe obesity, defined as a body mass index > or = 35 kg/m2, is frequently associated with various biological abnormalities, particularly in the presence of intra-abdominal adiposity. The most important disorders belong to the so-called insulin resistance syndrome, metabolic syndrome or syndrome X: hyperinsulinaemia, impaired glucose tolerance or type 2 diabetes, dyslipidaemias, hyperuricaemia, hyperfibrinogenaemia. All these metabolic abnormalities are considered as cardiovascular risk factors. They are also correlated with the severity of the liver steatosis which is commonly observed in individuals with severe obesity. We report our experience of the evolution of these metabolic abnormalities after a marked weight loss induced by gastroplasty. We will analyse the favourable effects of bariatric surgery on insulin sensitivity, biological components of the metabolic syndrome, type 2 diabetes and liver steatosis.

[How I explore ... the different forms of sugar diabetes: clinical and biological differental diagnosis]. / Comment j'explore ... les différentes formes de diabète sucré: diagnostic différentiel clinique et biologique.

Owing to the increasing prevalence of diabetes mellitus and the various aspects of this disease, we present a practical approach which allows the clinician to more easily differentiate type 1 diabetes, type 2 diabetes and secondary diabetes of pancreatic origin, i.e. the most common forms of diabetes mellitus. Such an approach uses simple diagnostic criteria, based upon both clinical characteristics (family history, personal history, clinical presentation) and biological markers (C-peptide, autoantibodies,...). A right diagnosis should allow to optimize the management of the diabetic patient.

Nonalcoholic steatohepatitis and insulin resistance: interface between gastroenterologists and endocrinologists.

Nonalcoholic steatohepatitis (NASH), along with other forms of nonalcoholic fatty liver disease, is an increasingly common clinico-pathological syndrome. It is frequently associated with obesity, especially visceral fat, and type 2 diabetes, and is intimately related to markers of the insulin resistance syndrome. Both the prevalence and the severity of liver steatosis are related to body mass index, waist circumference, hyperinsulinaemia, hypertriglyceridemia and impaired glucose tolerance. The pathophysiology of NASH involves two steps: 1) insulin resistance, which causes steatosis; 2) and oxidative stress, which produces lipid peroxidation and activates inflammatory cytokines. The identification of subjects who may progress from fatty liver to NASH, and from NASH to fibrosis/cirrhosis is an important clinical challenge as well as the finding of appropriate therapy that could prevent such deleterious process. Substantial weight loss is accompanied by a marked attenuation of insulin resistance and related metabolic syndrome and, concomitantly, by an important regression of liver steatosis in most patients, although mild inflammation may be detected in some subjects. Thus, NASH may be considered as another disease of affluence, as is the insulin resistance syndrome and perhaps being part of it.

Severe/extreme obesity: a medical disease requiring a surgical treatment?

Obesity poses a serious health hazard and its treatment is often disappointing. Surgical approaches have been proposed for treating severe obesity (body mass index or BMI > or = 35 kg/m2) with comorbidities or extreme obesity (BMI > or = 40 kg/m2). Before accepting bariatric surgery as alternative treatment, the four following prerequisites should be met: 1. the medical condition is serious enough; 2. it can not be treated satisfactorily with classical means; 3. the surgical treatment is effective in improving the clinical situation; and 4. bariatric surgery is safe enough, so that the benefits clearly outweigh the risks. On the basis of the literature and our own experience, it appears that gastric reduction surgery may be considered as a valuable alternative for treating severe/extreme obesity, despite the possible occurrence of perioperative and, more frequently, late complications, provided that it is performed by an experienced and multidisciplinary team in well-selected patients.