The advantages of physical exercise as a preventive strategy against NAFLD in postmenopausal women.

BACKGROUND: The prevalence and severity of nonalcoholic fatty liver disease (NAFLD) increase in women after menopause. This narrative review discusses the causes and consequences of NAFLD in postmenopausal women and describes how physical activity can contribute to its prevention. METHODS: The authors followed the narrative review method to perform a critical and objective analysis of the current knowledge on the topic. The Medical Subject Heading keywords 'physical exercise', 'menopause', 'hormone replacement therapy', 'estradiol' and 'NAFLD' were used to establish a conceptual framework. The databases used to collect relevant references included Medline and specialized high-impact journals. RESULTS: Higher visceral adiposity, higher rate of lipolysis in adipose tissue after oestrogen drop and changes in the expression of housekeeping proteins involved in hepatic lipid management are observed in women after menopause, contributing to NAFLD. Excessive liver steatosis leads to hepatic insulin resistance, oxidative stress and inflammation, accelerating NAFLD progression. Physical activity brings beneficial effects against several postmenopausal-associated complications, including NAFLD progression. Aerobic and resistance exercises partially counteract alterations induced by metabolic syndrome in sedentary postmenopausal women, impacting NAFLD progression and severity. CONCLUSIONS: With the increased global obesity epidemic in developing countries, NAFLD is becoming a severe problem with increased prevalence in women after menopause. Evidence shows that physical activity may delay NAFLD development and severity in postmenopausal women, although the prescription of age-appropriate physical activity programmes is advisable to assure the health benefits.

Exploring Liver Mitochondrial Function by 13C-Stable Isotope Breath Tests: Implications in Clinical Biochemistry.

The liver is at the crossroad of key metabolic processes, which include detoxification, glycolipidic storage and export, and protein synthesis. The gut-liver axis, moreover, provides hepatocytes with a series of bacterial products and metabolites, which contribute to maintain liver function in health and disease. Breath tests (BTs) are developed as diagnostic tools for indirect, rapid, noninvasive assessment of several metabolic processes in the liver. BTs monitor the appearance of CO2 in breath as a marker of a specific substrate metabolized in the liver, typically within microsomes, cytosol, or mitochondria. The noninvasiveness of BTs originates from the use of the, nonradioactive, naturally occurring stable isotope 13C marking a specific substrate which is metabolized in the liver, leading to the appearance of 13CO2 in expired air. Some substrates (ketoisocaproic acid, methionine, and octanoic acid) provide information about dynamic liver mitochondrial function in health and disease. In humans, the application of 13C-breath tests ranges from nonalcoholic and alcoholic liver diseases to liver cirrhosis, hepatocarcinoma, preoperative and postoperative assessment of liver function, and drug-induced liver damage. 13C-BTs are an indirect, cost-effective, and easy method to evaluate dynamic liver function and gastric kinetics in health and disease, with ongoing studies focusing on further applications in clinical medicine.

Protocols for Mitochondria as the Target of Pharmacological Therapy in the Context of Nonalcoholic Fatty Liver Disease (NAFLD).

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent metabolic chronic liver diseases in developed countries and puts the populations at risk of progression to liver necro-inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Mitochondrial dysfunction is involved in the onset of NAFLD and contributes to the progression from NAFLD to nonalcoholic steatohepatitis (NASH). Thus, liver mitochondria could become the target for treatments for improving liver function in NAFLD patients. This chapter describes the most important steps used for potential therapeutic interventions in NAFLD patients, discusses current options gathered from both experimental and clinical evidence, and presents some novel options for potentially improving mitochondrial function in NAFLD.

Multiplying effects of COVID-19 lockdown on metabolic risk and fatty liver.

BACKGROUND: Social containment measures imposed in Europe during the lockdown to face COVID-19 pandemic can generate long-term potential threats for metabolic health. METHODS: A cohort of 494 non-COVID-19 subjects living in 21 EU countries were interviewed by an anonymous questionnaire exploring anthropometric and lifestyle changes during 1-month lockdown. A subgroup of 41 overweight/obese Italian subjects with previously diagnosed nonalcoholic fatty liver (NAFLD) joined the study following a 12-month follow-up period promoting weight loss by healthy lifestyle. RESULTS: During the lockdown, body weight increased in 55% of subjects (average 2.4 ± 0.9 kg). Weight change increased with age, but not baseline body mass index. Subjects living in Italy had greater weight gain than those living in other European Countries. Weight gain during the lockdown was highest in subjects reporting no physical activity, and low adherence to Mediterranean diet. In the NAFLD group, weight gain occurred in 70% of cases. Subjects reporting weight loss during lockdown had decreased fatty liver score at 3 months before the lockdown, as compared with 1 year before. CONCLUSIONS: Strict measures of social containment-even short-term-pave the way to the increased risk of metabolic abnormalities in the medium-long term. In this context, adherence to Mediterranean diet and regular physical activity play a protective role both in terms of weight gain and fatty liver development/progression, with implication for primary and secondary prevention. When adopting measures imposing social containment, intensive educational campaigns must increase public awareness about beneficial effects of healthy lifestyles.

Adiponectin involved in portal flow hepatic extraction of 13C-methacetin in obesity and non-alcoholic fatty liver.

Obesity and non-alcoholic fatty liver disease (NAFLD) are high prevalence, inter-related conditions at increased risk for advanced liver diseases and related mortality. Adiponectin and leptin have divergent roles in the pathogenesis of fat accumulation and NAFLD. However, the relationships between body and liver fat accumulation, early modification of liver function and unbalanced adipokine levels are still scarcely explored. We studied by (13C)-methacetin breath test ((13C)-MBT) 67 adults stratified according to body mass index, and to presence/absence of ultrasonographic nonalcoholic fatty liver disease (uNAFLD). uNAFLD was detected in 20%, 73% and 96% of normal weight, overweight and obese subjects, respectively. The delta over baseline after 15 min (DOB15), a marker of hepatic extraction efficiency from portal blood flow, was lower in obese than in normal weight subjects, and in subjects with-, as compared to those without uNAFLD. The cumulative percent dose recovery after 30 min (cPDR30), a marker of liver microsomal function, was lower in uNAFLD patients. DOB15 was positively correlated with adiponectin levels in obese and in uNAFLD patients. uNAFLD patients also showed a positive correlation between cPDR30 values and adiponectin. Our data indicate the existence of early alterations of liver function in obese and in patients with uNAFLD. These dysfunctions are linked to altered leptin/adiponectin balance and can be identified noninvasively by (13C)-MBT.

(13C)-Methacetin breath test provides evidence of subclinical liver dysfunction linked to fat storage but not lifestyle.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is characterised by the presence of hepatic steatosis in the absence of other causes of secondary hepatic fat accumulation, and is usually associated with visceral, metabolically active obesity. However, the subclinical effects of body and liver fat accumulation on liver function are still unclear. METHODS: We used orally administered (13C)-methacetin and breath test to quantify the efficiency of hepatic extraction from portal blood flow and liver microsomal function in 81 participants, in relation to presence/absence of ultrasonographic NAFLD, extent of body fat accumulation, insulin resistance, dietary models, and lifestyle. RESULTS: NAFLD was present in 23% of participants with normal weight, and prevalence increased with body fat and insulin resistance. Fat accumulation, NAFLD, and insulin resistance were associated with decreased hepatic extraction efficiency, and liver microsomal function was impaired in moderate-to-severe NAFLD. Caloric intake, dietary models, and lifestyles had a minor role in promoting functional changes. CONCLUSIONS: The interplay between body fat accumulation, insulin resistance, and NAFLD is linked with altered hepatic extraction efficiency from blood flow and deranged microsomal function. Non-invasive diagnosis of subclinical alterations of liver function is relevant for primary and secondary prevention measures. Furthermore, the occurrence of NAFLD in lean individuals and the evidence that caloric intake, dietary models, and lifestyle played a minor role require further studies exploring the role of environmental factors in the natural history of these diseases. LAY SUMMARY: Obesity is progressively increasing worldwide and is paralleled by fat accumulation in the liver (non-alcoholic fatty liver disease [NAFLD]), the most common chronic liver disease worldwide. NAFLD can alter liver structure and function, with a variety of consequences ranging from asymptomatic and subclinical alterations to cirrhosis and cancer. (13C)-Methacetin breath test, a non-invasive diagnostic tool, can reveal early subclinical alterations of liver dynamic function in individuals with obesity and in patients with NAFLD.

Physical Activity Modulating Lipid Metabolism in Gallbladder Diseases.

Physical activity encompasses a series of overall benefits on cardiovascular health and metabolic disorders. Research has recently focused on the hepatobiliary tract, as an additional target of the health-related outcomes of different types of physical exercise. Here, we focus on the global features of physical activity with respect to exercise modality and intensity, and on studies linking physical activity to lipid metabolism, gallbladder diseases (gallstones, symptoms, complications and health-related quality of life), gallbladder motor-function, enterohepatic circulation of bile acids, and systemic metabolic inflammation. Additional studies need to unravel the pathophysiological mechanisms involved in both beneficial and harmful effects of physical activity in populations with different metabolic conditions.

Aging and nutrition. Paving the way to better health.

Sufficient caloric intake is important to maintain the balanced health status, especially during the period of aging, as aging and sickness share paths. Maintaining adequate nutritional balance is the best preventive measure to counteract the risk of malnutrition. There are several causes for malnutrition in elderly people, and some techniques such as anthropometric measurements, laboratory and clinical parameters could help to diagnose malnutrition in these patients. The use of a simple validated questionnaire called the 'Mini Nutritional Assessment' measures the nutritional status of elderly patients. In this review, we discuss about the malnutrition in elderly people with and without a known cause and we present some of nutritional intervention. There are promising strategies that help overcoming malnutrition.

Increased Colonic Permeability and Lifestyles as Contributing Factors to Obesity and Liver Steatosis.

Intestinal permeability (IP) is essential in maintaining gut-metabolic functions in health. An unequivocal evaluation of IP, as marker of intestinal barrier integrity, however, is missing in health and in several diseases. We aimed to assess IP in the whole gastrointestinal tract according to body mass index (BMI) and liver steatosis. In 120 patients (61F:59M; mean age 45 ± SEM 1.2 years, range: 18-75), IP was distinctively studied by urine recovery of orally administered sucrose (SO, stomach), lactulose/mannitol ratio (LA/MA, small intestine), and sucralose (SA, colon). By triple quadrupole mass-spectrometry and high-performance liquid chromatography, we measured urinary recovery of saccharide probes. Subjects were stratified according to BMI as normal weight, overweight, and obesity, and answered questionnaires regarding dietary habits and adherence to the Mediterranean Diet. Liver steatosis was assessed by ultrasonography. IP at every gastrointestinal tract was similar in both sexes and decreased with age. Stomach and small intestinal permeability did not differ according to BMI. Colonic permeability increased with BMI, waist, neck, and hip circumferences and was significantly higher in obese than in lean subjects. As determined by logistic regression, the odds ratio (OR) of BMI increment was significantly higher in subjects in the highest tertile of sucralose excretion, also after adjusting for age and consumption of junk food. The presence of liver steatosis was associated with increased colonic permeability. Patients with lower score of adherence to Mediterranean diet had a higher score of 'junk food'. Intestinal permeability tended to increase in subjects with a lower adherence to Mediterranean diet. In conclusion, colonic (but not stomach and small intestinal) permeability seems to be linked to obesity and liver steatosis independently from dietary habits, age, and physical activity. The exact role of these last factors, however, requires specific studies focusing on intestinal permeability. Results should pave the way to both primary prevention measures and new therapeutic strategies in metabolic and liver diseases.

Childhood obesity, cardiovascular and liver health: a growing epidemic with age.

BACKGROUND: The frequency of childhood obesity has increased over the last 3 decades, and the trend constitutes a worrisome epidemic worldwide. With the raising obesity risk, key aspects to consider are accurate body mass index classification, as well as metabolic and cardiovascular, and hepatic consequences. DATA SOURCES: The authors performed a systematic literature search in PubMed and EMBASE, using selected key words (obesity, childhood, cardiovascular, liver health). In particular, they focused their search on papers evaluating the impact of obesity on cardiovascular and liver health. RESULTS: We evaluated the current literature dealing with the impact of excessive body fat accumulation in childhood and across adulthood, as a predisposing factor to cardiovascular and hepatic alterations. We also evaluated the impact of physical and dietary behaviors starting from childhood on cardio-metabolic consequences. CONCLUSIONS: The epidemic of obesity and obesity-related comorbidities worldwide raises concerns about the impact of early abnormalities during childhood and adolescence. Two key abnormalities in this context include cardiovascular diseases, and nonalcoholic fatty liver disease. Appropriate metabolic screenings and associated comorbidities should start as early as possible in obese children and adolescents. Nevertheless, improving dietary intake and increasing physical activity performance are to date the best therapeutic tools in children to weaken the onset of obesity, cardiovascular diseases, and diabetes risk during adulthood.

Circulating CRP Levels Are Associated with Epicardial and Visceral Fat Depots in Women with Metabolic Syndrome Criteria.

Sexual dimorphism accounts for significant differences in adipose tissue mass and distribution. However, how the crosstalk between visceral and ectopic fat depots occurs and which are the determinants of ectopic fat expansion and dysfunction remains unknown. Here, we focused on the impact of gender in the crosstalk between visceral and epicardial fat depots and the role of adipocytokines and high-sensitivity C-reactive protein (hs-CRP). A total of 141 outward patients (both men and women) with one or more defining criteria for metabolic syndrome (MetS) were consecutively enrolled. For all patients, demographic and clinical data were collected and ultrasound assessment of visceral adipose tissue (VFth) and epicardial fat (EFth) thickness was performed. Hs-CRP and adipocytokine levels were assessed by enzyme-linked immunosorbent assay (ELISA). Men were characterized by increased VFth and EFth (p-value < 0.001 and 0.014, respectively), whereas women showed higher levels of adiponectin and leptin (p-value < 0.001 for both). However, only in women VFth and EFth significantly correlated between them (p = 0.013) and also with leptin (p < 0.001 for both) and hs-CRP (p = 0.005 and p = 0.028, respectively). Linear regression confirmed an independent association of both leptin and hs-CRP with VFth in women, also after adjustment for age and MetS (p = 0.012 and 0.007, respectively). In conclusion, men and women present differences in epicardial fat deposition and systemic inflammation. An intriguing association between visceral/epicardial fat depots and chronic low-grade inflammation also emerged. In women Although a further validation in larger studies is needed, these findings suggest a critical role of sex in stratification of obese/dysmetabolic patients.

Faster Detection of Helicobacter pylori Infection by 13 C-Urea Breath Test. Comparing Short versus Standard Sampling Time.

BACKGROUND AND AIMS: 13 C-Urea Breath Test (UBT) is a non-invasive, highly accurate and recommended test to detect Helicobacter pylori (H. pylori) infection and to confirm post-therapy eradication. However, differences exist in terms of manufacturers, dose of labelled urea, addition of citric acid, solid vs. liquid formulation, and sampling times of breath samples. In this study, we compared the diagnostic accuracy of "short" (15 minutes) vs. "standard" (30 minutes) time for a single type of liquid UBT. METHODS: We compared the performance of a single UBT type (BREATHQUALITY, AB Analitica, Padua, Italy, 10 mL of 75 mg 13 C-Urea and 1.4 g citric acid) during a "short" vs. "standard" breath sampling time. Enrolled were 151 subjects requiring UBT as naïve (N=92) or post-eradication (N=59) checks. RESULTS: UBT at 15 and 30 minutes were highly comparable, showing optimal correlation in all subsets of patients (i.e. naïve vs. post eradication, negative vs. post eradication check). One discrepant result occurred at the borderline zone of the DOB 4‰, but proved to be true positive at a later confirmation by a second UBT and stool antigen test. CONCLUSIONS: By shortening the testing time of BREATHQUALITY to 15 minutes (-50%) comparable accuracy will be maintained and in addition, it will bring some benefits to patients' waiting lists, compliance, and hospital staff.

Non-Alcoholic Fatty Liver Disease in Non-Obese Individuals: Prevalence, Pathogenesis and Treatment.

Non-alcoholic fatty liver disease (NAFLD) parallels comorbidities such as metabolic syndrome, dyslipidaemia or diabetes. Although NAFLD is very prevalent in overweight-obese individuals (i.e. body mass index ≥25 kg/m2), recent studies point to the presence of NAFLD in non-obese individuals, for both the Asian (<25 kg/m2) and Caucasian (<30 kg/m2) populations. This paper discusses the pathogenic pathways and current treatment options of NAFLD in non-obese populations. In this respect, non-obese subjects also need to undergo the medical screening for NAFLD. Across the scientific community, we aim to promote the advancement of knowledge in this emerging field.

Critical Care Aspects of Gallstone Disease.

Approximately twenty per cent of adults have gallstones making it one of the most prevalent gastrointestinal diseases in Western countries. About twenty per cent of gallstone patients requires medical, endoscopic, or surgical therapies such as cholecystectomy due to the onset of gallstone-related symptoms or gallstone-related complications. Thus, patients with symptomatic, uncomplicated or complicated gallstones, regardless of the type of stones, represent one of the largest patient categories admitted to European hospitals. This review deals with the important critical care aspects associated with a gallstone-related disease.

Gastrointestinal defects in gallstone and cholecystectomized patients.

BACKGROUND AND AIM: Several gallstone patients complain of dyspeptic symptoms, irrespective of the presence of typical colicky pain. Symptoms often persist after a cholecystectomy. Systematic studies on dyspepsia and dynamic gastrointestinal motor function are missing in gallstone patients with preserved gallbladder or after a cholecystectomy. MATERIALS AND METHODS: Forty-six gallstone patients (age 55 ± 2 years; 15M, 31F) and 24 cholecystectomized patients (age 57 ± 2 years; 6M, 18F) (no difference in type and volume of gallstones between the two groups) were compared against a group of 65 healthy controls (age 51 ± 2 years; 30M, 35F). Dyspepsia occurring in the prior months was assessed by a questionnaire, gastric and gallbladder emptying by functional ultrasonography and orocecal transit time by a hydrogen breath test using a lactulose-enriched standard liquid meal. RESULTS: Gallstone patients had significantly greater dyspepsia, fasting and residual gallbladder volumes, and slower gallbladder emptying, gastric emptying and small intestinal transit time than controls. In cholecystectomized patients, gastric emptying further delayed, compared to gallstone patients and controls. CONCLUSION: Gallstone patients with the gallbladder "in situ" or after a cholecystectomy display dyspeptic symptoms. Symptoms are associated with multiple gastrointestinal motility defects involving the gallbladder, stomach and small intestine. After cholecystectomy, gastric emptying worsens.

Exercising the hepatobiliary-gut axis. The impact of physical activity performance.

BACKGROUND: Physical inactivity puts the populations at risk of several health problems, while regular physical activity brings beneficial effects on cardiovascular disease, mortality and other health outcomes, including obesity, glycaemic control and insulin resistance. The hepatobiliary tract is greatly involved in several metabolic aspects which include digestion and absorption of nutrients in concert with intestinal motility, bile acid secretion and flow across the enterohepatic circulation and intestinal microbiota. Several metabolic abnormalities, including nonalcoholic fatty liver as well as cholesterol cholelithiasis, represent two conditions explained by changes of the aforementioned pathways. MATERIALS AND METHODS: This review defines different training modalities and discusses the effects of physical activity in two metabolic disorders, that is nonalcoholic fatty liver disease (NAFLD) and cholelithiasis. Emphasis is given to pathogenic mechanisms involving intestinal bile acids, microbiota and inflammatory status. RESULTS: A full definition of physical activity includes the knowledge of aerobic and endurance exercise, metabolic equivalent tasks, duration, frequency and intensity, beneficial and harmful effects. Physical activity influences the hepatobiliary-gut axis at different levels and brings benefits to fat distribution, liver fat and gallbladder disease while interacting with bile acids as signalling molecules, intestinal microbiota and inflammatory changes in the body. CONCLUSIONS: Several beneficial effects of physical activity are anticipated on metabolic disorders linking liver steatosis, gallstone disease, gut motility, enterohepatic circulation of signalling bile acids in relation to intestinal microbiota and inflammatory changes.

Bile Acid Physiology.

The primary bile acids (BAs) are synthetized from colesterol in the liver, conjugated to glycine or taurine to increase their solubility, secreted into bile, concentrated in the gallbladder during fasting, and expelled in the intestine in response to dietary fat, as well as bio-transformed in the colon to the secondary BAs by the gut microbiota, reabsorbed in the ileum and colon back to the liver, and minimally lost in the feces. BAs in the intestine not only regulate the digestion and absorption of cholesterol, triglycerides, and fat-soluble vitamins, but also play a key role as signaling molecules in modulating epithelial cell proliferation, gene expression, and lipid and glucose metabolism by activating farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor-1 (GPBAR-1, also known as TGR5) in the liver, intestine, muscle and brown adipose tissue. Recent studies have revealed the metabolic pathways of FXR and GPBAR-1 involved in the biosynthesis and enterohepatic circulation of BAs and their functions as signaling molecules on lipid and glucose metabolism.

Bile Acids and Cancer: Direct and Environmental-Dependent Effects.

Bile acids (BAs) regulate the absorption of fat-soluble vitamins, cholesterol and lipids but have also a key role as singalling molecules and in the modulation of epithelial cell proliferation, gene expression and metabolism. These homeostatic pathways, when disrupted, are able to promote local inflammation, systemic metabolic disorders and, ultimately, cancer. The effect of hydrophobic BAs, in particular, can be linked with cancer in several digestive (mainly oesophagus, stomach, liver, pancreas, biliary tract, colon) and extra-digestive organs (i.e. prostate, breast) through a complex series of mechanisms including direct oxidative stress with DNA damage, apoptosis, epigenetic factors regulating gene expression, reduced/increased expression of nuclear receptors (mainly farnesoid X receptor, FXR) and altered composition of gut microbiota, also acting as a common interface between environmental factors (including diet, lifestyle, exposure to toxics) and the molecular events promoting cancerogenesis. Primary prevention strategies (i.e. changes in dietary habits and lifestyle, reduced exposure to environmental toxics) mainly able to modulate gut microbiota and the epigenome, and the therapeutic use of hydrophilic BAs to counterbalance the negative effects of the more hydrophobic BAs might be, in the near future, part of useful tools for cancer prevention and management.