https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.20701

Design and validation of a histological scoring system for nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is present in up to one third of the general population and in the majority of patients with metabolic risk factors such as obesity and diabetes. Insulin resistance is a key pathogenic factor resulting in hepatic fat accumulation. Recent evidence demonstrates NAFLD in turn, exacerbates hepatic insulin resistance and often precedes glucose intolerance. Once hepatic steatosis is established, other factors including oxidative stress, mitochondrial dysfunction, gut-derived lipopolysaccharide and adipocytokines, may promote hepatocellular damage, inflammation and progressive liver disease. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies, however staging the disease requires a liver biopsy. NAFLD is associated with an increased risk of all-cause death, probably because of complications of insulin resistance such as vascular disease, as well as due to cirrhosis and hepatocellular carcinoma, which occurs in a minority of patients. NAFLD is also now recognized to account for a substantial proportion of patients previously diagnosed with 'cryptogenic cirrhosis'. Diabetes, obesity and the necroinflammatory form of NAFLD known as non-alcoholic steatohepatitis, are risk factors for progressive liver disease. Current treatment relies on weight loss and exercise, although various insulin-sensitizing medications appear promising. Further research is needed to identify which patients will achieve the most benefit from therapy.

Nonalcoholic fatty liver disease.

Lipid homeostasis in vertebrate cells is regulated by a family of membrane-bound transcription factors designated sterol regulatory element–binding proteins (SREBPs). SREBPs directly activate the expression of more than 30 genes dedicated to the synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids, as well as the NADPH cofactor required to synthesize these molecules (1–4). In the liver, three SREBPs regulate the production of lipids for export into the plasma as lipoproteins and into the bile as micelles. The complex, interdigitated roles of these three SREBPs have been dissected through the study of ten different lines of gene-manipulated mice. These studies form the subject of this review.

/pdf/srebps-activators-of-the-complete-program-of-cholesterol-and-1sop601qwq.pdf

SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver

Ten per cent of the world’s school-aged children are estimated to be carrying excess body fat (Fig. 1), with an increased risk for developing chronic disease. Of these overweight children, a quarter are obese, with a significant likelihood of some having multiple risk factors for type 2 diabetes, heart disease and a variety of other co-morbidities before or during early adulthood. The prevalence of overweight is dramatically higher in economically developed regions, but is rising significantly in most parts of the world. In many countries the problem of childhood obesity is worsening at a dramatic rate. Surveys during the 1990s show that in Brazil and the USA, an additional 0.5% of the entire child population became overweight each year. In Canada, Australia and parts of Europe the rates were higher, with an additional 1% of all children becoming overweight each year. The burden upon the health services cannot yet be estimated. Although childhood obesity brings a number of additional problems in its train – hyperinsulinaemia, poor glucose tolerance and a raised risk of type 2 diabetes, hypertension, sleep apnoea, social exclusion and depression – the greatest health problems will be seen in the next generation of adults as the present childhood obesity epidemic passes through to adulthood. Greatly increased rates of heart disease, diabetes, certain cancers, gall bladder disease, osteoarthritis, endocrine disorders and other obesityrelated conditions will be found in young adult populations, and their need for medical treatment may last for their remaining life-times. The costs to the health services, the losses to society and the burdens carried by the individuals involved will be great. The present report has been written to focus attention on the issue and to urge policy-makers to consider taking action before it is too late. Specifically, the report:

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1467-789X.2004.00133.x

Obesity in children and young people: a crisis in public health.

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.20466

Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity

Insulin sensitivity (euglycemic clamp, insulin infusion rate: 40 mU m(-2) min(-1)) was studied in 30 subjects with biopsy-proven nonalcoholic fatty liver disease (NAFLD), normal glucose tolerance, and a BMI <30 kg/m(2) Of those 30 subjects, 9 had pure fatty liver and 21 had evidence of steatohepatitis In addition, 10 patients with type 2 diabetes under good metabolic control and 10 healthy subjects were studied Most NAFLD patients had central fat accumulation, increased triglycerides and uric acid, and low HDL cholesterol, irrespective of BMI Glucose disposal during the clamp was reduced by nearly 50% in NAFLD patients, as well as in patients with normal body weight, to an extent similar to that of the type 2 diabetic patients Basal free fatty acids were increased, whereas insulin-mediated suppression of lipolysis was less effective (-69% in NAFLD vs -84% in control subjects; P = 0003) Postabsorptive hepatic glucose production (HGP), measured by [6,6-(2)H(2)]glucose, was normal In response to insulin infusion, HGP decreased by only 63% of basal in NAFLD vs 84% in control subjects (P = 0002) Compared with type 2 diabetic patients, NAFLD patients were characterized by lower basal HGP, but with similarly reduced insulin-mediated suppression of HGP There was laboratory evidence of iron overload in many NAFLD patients, but clinical, histological, and biochemical data (including insulin sensitivity) were not correlated with iron status Four subjects were heterozygous for mutation His63Asp of the HFE gene of familiar hemochromatosis We concluded that NAFLD, in the presence of normoglycemia and normal or moderately increased body weight, is characterized by clinical and laboratory data similar to those found in diabetes and obesity NAFLD may be considered an additional feature of the metabolic syndrome, with specific hepatic insulin resistance

/pdf/nonalcoholic-fatty-liver-disease-a-feature-of-the-metabolic-tls3hey2y6.pdf

Nonalcoholic fatty liver disease a feature of the metabolic syndrome

https://www.amjmed.com/article/S0002-9343(99)00271-5/pdf

Association of nonalcoholic fatty liver disease with insulin resistance

Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis

Background The impact on patient survival of an infectious disease (ID) team dedicated to the early management of severe sepsis/septic shock (SS/SS) in Emergency Department (ED) has yet to be assessed. Methods A quasiexperimental pre-post study was performed at the general ED of our hospital. During the pre phase (June 2013-July 2014), all consecutive adult patients with SS/SS were managed according to the standard of care, data were prospectively collected. During the post phase (August 2014-October 2015), patients were managed in collaboration with a dedicated ID team performing a bedside patient evaluation within 1 hour of ED arrival. Results Overall, 382 patients were included, 195 in the pre phase and 187 in the post phase. Median age was 82 years (interquartile range, 70-88). The most common infection sources were lung (43%) and urinary tract (17%); in 22% of cases, infection source remained unknown. During the post phase, overall compliance with the Surviving Sepsis Campaign (SSC) bundle and appropriateness of initial antibiotic therapy improved from 4.6% to 32% (P < .001) and from 30% to 79% (P < .001), respectively. Multivariate analysis showed that predictors of all-cause 14-day mortality were quick sepsis-related organ failure assessment ≥2 (hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.15-2.45; P = .007), serum lactate ≥2 mmol/L (HR, 2.13; 95% CI, 1.39-3.25; P < .001), and unknown infection source (HR, 2.07; 95% CI, 1.42-3.02; P < .001); being attended during the post phase was a protective factor (HR, 0.64; 95% CI, 0.43-0.94; P = .026). Conclusion Implementation of an ID team for the early management of SS/SS in the ED improved the adherence to SSC recommendations and patient survival.

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Infectious Diseases Team for the Early Management of Severe Sepsis and Septic Shock in the Emergency Department

During the last 20 years there has been much interest in nutritional treatment for patients with advanced cirrhosis. Most studies have measured the potential benefit of nutritional supplements of dietary proteins, generic protein hydrolysates, or specific branched-chain amino acid (BCAA)-enriched formulas in regard to nutritional parameters and hepatic encephalopathy. The issue is not definitively settled; data are conflicting and meta-analyses have failed to produce unequivocal results. A consensus review, recently produced under the auspices of the European Society for Parenteral and Enteral Nutrition, concluded that: (1) patients with cirrhosis tend to be hypermetabolic, and a higher-than-normal supply of dietary proteins is needed to achieve nitrogen balance; (2) most patients tolerate a normal or even increased dietary protein intake, without risk of hepatic encephalopathy; (3) a modified eating pattern, based on several meals and a late evening snack, is useful; (4) in severely malnourished patients, amino acid supplements may be considered to provide the necessary amount of proteins to meet protein requirements; (5) in a few patients intolerant to the required protein intake, BCAA supplements may be considered to provide the necessary nitrogen intake without detrimental effects on the mental state, perhaps even improving it. Future studies are needed to quantify the advantage of nutritional support with amino acids or BCAA supplements on overall well-being, complications, and ultimately survival with a long-lasting disease where self-perceived health-related quality of life is a major outcome.

Mara Brizi

Papers

Nonalcoholic fatty liver disease a feature of the metabolic syndrome

Association of nonalcoholic fatty liver disease with insulin resistance

Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis

Infectious Diseases Team for the Early Management of Severe Sepsis and Septic Shock in the Emergency Department

Nutritional treatment with branched-chain amino acids in advanced liver cirrhosis.