Effect of bariatric surgery on NAFLD/NASH: a single-centre observational prospective cohort study.

INTRODUCTION: The prevalence of non-alcoholic fatty liver disease (NAFLD) ranges from 25% in the general population to 90% in patients with obesity scheduled for bariatric surgery. NAFLD can progress towards non-alcoholic steatohepatitis (NASH) associated with complications such as cirrhosis, hepatocellular carcinoma and cardiovascular disease. To date, losing weight and lifestyle modifications are the best known treatments for NASH. Bariatric surgery significantly improves NAFLD/NASH in the short term. However, the extent of this improvement is not yet clear and long-term data on the natural course of NAFLD/NASH after bariatric surgery are lacking. The factors involved in NAFLD/NASH regression after bariatric surgery have not been elucidated. METHODS AND ANALYSIS: This is an observational prospective cohort study including patients scheduled for bariatric surgery. Extensive metabolic and cardiovascular analyses will be carried out including measurements of carotid intima media thickness and pulse wave velocity. Genomic, proteomic, lipidomic and metabolomic studies will be done. Microbioma analyses before and 1 year after surgery will be done. Transient elastography measurements will be performed before and at 1, 3 and 5 years after surgery. For those with an elevated preoperative transient elastography measurement by Fibroscan, a laparoscopic liver biopsy will be performed during surgery. Primary outcome measures are the change of steatosis and liver fibrosis 5 years after surgery. Secondary outcome measure is the comparison of the transient elastography measurements with the NAFLD Activity Score from the biopsies. ETHICS AND DISSEMINATION: The protocol has been approved by the Medical Research Ethics Committees United, Nieuwegein, on 1 March 2022 (registration code R21.103/NL79423.100.21). The study results will be submitted for publication in peer-reviewed journals and data will be presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05499949.

Evaluation of nonalcoholic fatty liver disease (NAFLD) in severe obesity using noninvasive tests and imaging techniques.

The prevalence of nonalcoholic fatty liver disease (NAFLD) and the more severe and inflammatory type, nonalcoholic steatohepatitis (NASH), is increasing rapidly. Especially in high-risk patients, that is those with obesity, metabolic syndrome, and type 2 diabetes mellitus, the prevalence of NAFLD can be as high as 80% while NASH may be present in 20% of these subjects. With the worldwide increase of obesity, it is most likely that these numbers will rise. Since advanced stages of NAFLD and NASH are strongly associated with morbidity and mortality-in particular, cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma-it is of great importance to identify subjects at risk. A great variety of noninvasive tests has been published to diagnose NAFLD and NASH, especially using blood- and imaging-based tests. Liver biopsy remains the gold standard for NAFLD/NASH. This review aims to summarize the different mechanisms leading to NASH and liver fibrosis, the different noninvasive liver tests to diagnose and evaluate patients with severe obesity.

Liver failure caused by prolonged state of malnutrition following bariatric surgery.

Bariatric surgery is an effective tool in the treatment of patients with morbid obesity. In these case reports we describe 2 patients who developed liver failure after currently-practiced types of bariatric surgery, caused by a prolonged state of malnutrition provoked by psychiatric problems. Despite intensive guidance of a psychologist and dieticians after surgery, our patients deteriorated psychologically, resulting in a prolonged state of severe malnutrition and anorexia. Finally, a state of starvation was reached, passing a critical level of the liver capacity. Patients who present with signs of severe protein malnutrition after bariatric surgery should be closely monitored and checked for nutritional status. Specific attention should be given to patients who develop psychiatric problems post-bariatric surgery. If refeeding does not result in clinical improvement, reversal surgery should be considered in a timely manner.

The postprandial situation as a pro-inflammatory condition / La situación posprandial como condición proinflamatoria

Postprandial lipemia has been associated with cardiovascular disease. The current pathophysiological concept is that postprandial remnant lipoproteins migrate into the subendothelial space and that remnants activate circulating leukocytes and endothelial cells. Activated monocytes adhere to endothelial adhesion molecules, facilitating subendothelial migration of monocytes. These cells differentiate into macrophages, with the risk of foam cell formation, due to uptake of remnants and modified lipoproteins. Evidence is emerging that specific interventions may reduce the atherogenic postprandial inflammation. Fruits rich in polyphenols, virgin olive oil, carotenoids and exercise have recently been found to reduce postprandial inflammation. Pharmaceutical interventions with fibrates or statins not only improve the overall lipid profile, but reduce postprandial inflammation as well. This review will deal with the current concept of postprandial inflammation in relation to the development of atherosclerosis and potential interventions to reduce postprandial inflammation

La lipidemia posprandial está relacionada con la enfermedad cardiovascular. El concepto patofisiológico actual es que las partículas remanentes traspasan el endotelio, activan los leucocitos y las células endoteliales. Los monocitos activados se adhieren a la paredendotelial por mediación de moléculas de adhesión, facilitando así la migración de los monocitos al espacio subendotelial. Estas células se transforman en macrófagos, convirtiéndose definitivamente en células espumosas después de haber internalizado las partículas remanentes y otras lipoproteínas modificadas. Recientes estudios sugieren que existen intervenciones efectivas para modular la inflamación posprandial, y de esta forma rebajar el riesgo cardiovascular. Frutas ricas en polifenoles, aceite de oliva virgen, el caroteno y el ejercicio son ejemplos que han demostrado una reducción de la inflamación posprandial. El tratamiento con estatinas y fibratos no solo mejora el perfil lipídico, sino que también rebaja la lipidemia posprandial. Esta revisión describe los recientes conceptos de la inflamación posprandial relacionada con la generación de ateroesclerosis y también trata las intervenciones que pueden influir positivamente en la inflamación posprandial

The postprandial situation as a pro-inflammatory condition.

Postprandial lipemia has been associated with cardiovascular disease. The current pathophysiological concept is that postprandial remnant lipoproteins migrate into the subendothelial space and that remnants activate circulating leukocytes and endothelial cells. Activated monocytes adhere to endothelial adhesion molecules, facilitating subendothelial migration of monocytes. These cells differentiate into macrophages, with the risk of foam cell formation, due to uptake of remnants and modified lipoproteins. Evidence is emerging that specific interventions may reduce the atherogenic postprandial inflammation. Fruits rich in polyphenols, virgin olive oil, carotenoids and exercise have recently been found to reduce postprandial inflammation. Pharmaceutical interventions with fibrates or statins not only improve the overall lipid profile, but reduce postprandial inflammation as well. This review will deal with the current concept of postprandial inflammation in relation to the development of atherosclerosis and potential interventions to reduce postprandial inflammation.

Endocrine autoimmune disease: genetics become complex.

The endocrine system is a frequent target in pathogenic autoimmune responses. Type 1 diabetes and autoimmune thyroid disease are the prevailing examples. When several diseases cluster together in one individual, the phenomenon is called autoimmune polyglandular syndrome. Progress has been made in understanding the genetic factors involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases such as autoimmune polyglandular syndrome type 1, immunodysregulation, polyendocrinopathy, enteropathy, X-linked and primary immune deficiencies helped uncover the role of key regulators in the preservation of immune tolerance. Alleles of the major histocompatibility complex have been known to contribute to the susceptibility to most forms of autoimmunity for more than 3 decades. Furthermore, sequencing studies revealed three non-major histocompatibility complex loci and some disease specific loci, which control T lymphocyte activation or signalling. Recent genome-wide association studies (GWAS) have enabled acceleration in the identification of novel (non-HLA) loci and hence other relevant immune response pathways. Interestingly, several loci are shared between autoimmune diseases, and surprisingly some work in opposite direction. This means that the same allele which predisposes to a certain autoimmune disease can be protective in another. Well powered GWAS in type 1 diabetes has led to the uncovering of a significant number of risk variants with modest effect. These studies showed that the innate immune system may also play a role in addition to the adaptive immune system. It is anticipated that next generation sequencing techniques will uncover other (rare) variants. For other autoimmune disease (such as autoimmune thyroid disease) GWAS are clearly needed.

Early insulin sensitivity after restrictive bariatric surgery, inconsistency between HOMA-IR and steady-state plasma glucose levels.

BACKGROUND: The low-grade inflammatory condition present in morbid obesity is thought to play a causative role in the pathophysiology of insulin resistance (IR). Bariatric surgery fails to improve this inflammatory condition during the first months after surgery. Considering the close relation between inflammation and IR, we conducted a study in which insulin sensitivity was measured during the first months after bariatric surgery. Different methods to measure IR shortly after bariatric surgery have given inconsistent data. For example, the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) levels have been reported to decrease rapidly after bariatric surgery, although clamp techniques have shown sustained insulin resistance. In the present study, we evaluated the use of steady-state plasma glucose (SSPG) levels to assess insulin sensitivity 2 months after bariatric surgery. METHODS: Insulin sensitivity was measured using HOMA-IR and SSPG levels in 11 subjects before surgery and at 26% excess weight loss (approximately 2 months after restrictive bariatric surgery). RESULTS: The SSPG levels after 26% excess weight loss did not differ from the SSPG levels before surgery (14.3 +/- 5.4 versus 14.4 +/- 2.7 mmol/L). In contrast, the HOMA-IR values had decreased significantly (3.59 +/- 1.99 versus 2.09 +/- 1.02). CONCLUSION: During the first months after restrictive bariatric surgery, we observed a discrepancy between the HOMA-IR and SSPG levels. In contrast to the HOMA-IR values, the SSPG levels had not improved, which could be explained by the ongoing inflammatory state after bariatric surgery. These results suggest that during the first months after restrictive bariatric surgery, HOMA-IR might not be an adequate marker of insulin sensitivity.

Short-term overfeeding induces insulin resistance in weight-stable patients after bariatric surgery.

BACKGROUND: Short time overfeeding of rats rapidly leads to insulin resistance (IR). A study with healthy human volunteers, which we suggest are less susceptible for developing IR after short time overfeeding, did not show these effects on IR. Therefore a study population of weight-stable, former morbidly obese subjects (BMI 31.3 kg/m2), which were treated with bariatric surgery approximately 3 years ago was selected. METHODS: Eleven subjects were submitted to a 7-day overfeeding study, resulting in a 53% increase in caloric intake (1,227 +/- 394.4 to 1,879.2 +/- 298.4 kcal/day). During normal diet and after overfeeding, insulin sensitivity was measured using steady state plasma glucose (SSPG) levels. At these time points, BMI and waist/hip ratio together with plasma levels of inflammatory markers (CRP, AGP, LBP, and TNF-alpha receptors) and plasma leptin values were also measured. RESULTS: SSPG levels after overfeeding increased from 8.2 +/- 3.2 to 10.6 +/- 2.6 mmol/l (P < 0.05), indicating decreased insulin sensitivity after overfeeding. Fasting plasma insulin, glucose, circulating levels of inflammatory markers, BMI, and waist/hip ratio remained unchanged. CONCLUSIONS: This study shows that overfeeding in a group of weight-stable, former morbidly obese subjects 3 years after bariatric surgery results in decreased insulin sensitivity. The mechanisms behind decreased insulin sensitivity induced by overfeeding are poorly understood, but the present results reveal that a unique human model is available to study these mechanisms, leading to a better understanding of the pathophysiology of IR.