Non-alcoholic fatty liver (NAFLD) is the most common liver disease worldwide, progressing from simple steatosis to necroinflammation and fibrosis (leading to non-alcoholic steatohepatitis, NASH), and in some cases to cirrhosis and hepatocellular carcinoma Inflammation, oxidative stress and insulin resistance are involved in NAFLD development and progression NAFLD has been associated with several cardiovascular (CV) risk factors including obesity, dyslipidemia, hyperglycemia, hypertension and smoking NAFLD is also characterized by atherogenic dyslipidemia, postprandial lipemia and high-density lipoprotein (HDL) dysfunction Most importantly, NAFLD patients have an increased risk for both liver and CV disease (CVD) morbidity and mortality In this narrative review, the associations between NAFLD, dyslipidemia and vascular disease in NAFLD patients are discussed NAFLD treatment is also reviewed with a focus on lipid-lowering drugs Finally, future perspectives in terms of both NAFLD diagnostic biomarkers and therapeutic targets are considered

Non-alcoholic fatty liver disease and dyslipidemia: An update

The prevalence of excess body weight and the associated cancer burden have been rising over the past several decades globally. Between 1975 and 2016, the prevalence of excess body weight in adults-defined as a body mass index (BMI) ≥ 25 kg/m2 -increased from nearly 21% in men and 24% in women to approximately 40% in both sexes. Notably, the prevalence of obesity (BMI ≥ 30 kg/m2 ) quadrupled in men, from 3% to 12%, and more than doubled in women, from 7% to 16%. This change, combined with population growth, resulted in a more than 6-fold increase in the number of obese adults, from 100 to 671 million. The largest absolute increase in obesity occurred among men and boys in high-income Western countries and among women and girls in Central Asia, the Middle East, and North Africa. The simultaneous rise in excess body weight in almost all countries is thought to be driven largely by changes in the global food system, which promotes energy-dense, nutrient-poor foods, alongside reduced opportunities for physical activity. In 2012, excess body weight accounted for approximately 3.9% of all cancers (544,300 cases) with proportion varying from less than 1% in low-income countries to 7% or 8% in some high-income Western countries and in Middle Eastern and Northern African countries. The attributable burden by sex was higher for women (368,500 cases) than for men (175,800 cases). Given the pandemic proportion of excess body weight in high-income countries and the increasing prevalence in low- and middle-income countries, the global cancer burden attributable to this condition is likely to increase in the future. There is emerging consensus on opportunities for obesity control through the multisectoral coordinated implementation of core policy actions to promote an environment conducive to a healthy diet and active living. The rapid increase in both the prevalence of excess body weight and the associated cancer burden highlights the need for a rejuvenated focus on identifying, implementing, and evaluating interventions to prevent and control excess body weight.

Global patterns in excess body weight and the associated cancer burden.

The subcutaneous adipose tissue (SAT) is the largest and best storage site for excess lipids. However, it has a limited ability to expand by recruiting and/or differentiating available precursor ce...

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Impaired Adipogenesis and Dysfunctional Adipose Tissue in Human Hypertrophic Obesity.

Obesity is a risk factor for type 2 diabetes mellitus. Among obesity, visceral fat obesity, and ectopic fat obesity, it has been unclear which has the greatest effect on incident diabetes. In this historical cohort study of 8430 men and 7034 women, we investigated the effect of obesity phenotypes on incident diabetes. Obesity, visceral fat obesity, and ectopic fat obesity were defined as body mass index ≥25 kg/m2, waist circumference ≥90 cm in men or ≥80 cm in women, and having fatty liver diagnosed by abdominal ultrasonography, respectively. We divided the participants into eight groups according to the presence or absence of the three obesity phenotypes. During the median 5.8 years follow-up for men and 5.1 years follow-up for women, 286 men and 87 women developed diabetes. Compared to the non-obese group, the hazard ratios (HRs) of incident diabetes in the only-obesity, only-visceral fat obesity, only-ectopic fat obesity groups, and with all-three types of obesity group were 1.85 (95%CI 1.06–3.26, p = 0.05) in men and 1.79 (0.24–13.21, p = 0.60) in women, 3.41 (2.51–4.64, p < 0.001) in men and 2.30 (0.87–6.05, p = 0.12) in women, 4.74 (1.91–11.70, p < 0.001) in men and 13.99 (7.23–27.09, p < 0.001) in women and 10.5 (8.02–13.8, p < 0.001) in men and 30.0 (18.0–50.0, p < 0.001) in women. Moreover, the risk of incident diabetes of the groups with ectopic fat obesity were almost higher than that of the four groups without ectopic fat obesity. Ectopic fat obesity presented the greatest risk of incident type 2 diabetes.

Ectopic fat obesity presents the greatest risk for incident type 2 diabetes: a population-based longitudinal study.

Hepatic steatosis, the first step in the progression of nonalcoholic fatty liver disease, is characterized by triglyceride accumulation in hepatocytes and is highly prevalent in people with obesity. Although initially asymptomatic, hepatic steatosis is an important risk factor for the development of hepatic insulin resistance and type 2 diabetes mellitus and can also progress to more severe pathologies such as nonalcoholic steatohepatitis, liver fibrosis and cirrhosis; hepatic steatosis has, therefore, received considerable research interest in the past 20 years. The lipid accumulation that defines hepatic steatosis disturbs the function of the endoplasmic reticulum (ER) in hepatocytes, thereby generating chronic ER stress that interferes with normal cellular function. Although ubiquitous stress response mechanisms (namely, ER-associated degradation, unfolded protein response and autophagy) are the main processes for restoring cellular proteostasis, these mechanisms are unable to alleviate ER stress in the context of the fatty liver. Furthermore, ER stress and ER stress responses can promote lipid accumulation in hepatocytes in a counter-productive manner and could, therefore, be the origin of a vicious pathological cycle.

Endoplasmic reticulum proteostasis in hepatic steatosis.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Presentation of the disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). NAFLD is a hepatic manifestation of metabolic syndrome that includes central abdominal obesity along with other components. Up to 80% of patients with NAFLD are obese, defined as a body mass index (BMI) > 30 kg/m2. However, the distribution of fat tissue plays a greater role in insulin resistance than the BMI. The large amount of visceral adipose tissue (VAT) in morbidly obese (BMI > 40 kg/m2) individuals contributes to a high prevalence of NAFLD. Free fatty acids derived from VAT tissue, as well as from dietary sources and de novo lipogenesis, are released to the portal venous system. Excess free fatty acids and chronic low-grade inflammation from VAT are considered to be two of the most important factors contributing to liver injury progression in NAFLD. In addition, secretion of adipokines from VAT as well as lipid accumulation in the liver further promotes inflammation through nuclear factor kappa B signaling pathways, which are also activated by free fatty acids, and contribute to insulin resistance. Most NAFLD patients are asymptomatic on clinical presentation, even though some may present with fatigue, dyspepsia, dull pain in the liver and hepatosplenomegaly. Treatment for NAFLD and NASH involves weight reduction through lifestyle modifications, anti-obesity medication and bariatric surgery. This article reviews the available information on the biochemical and metabolic phenotypes associated with obesity and fatty liver disease. The relative contribution of visceral and liver fat to insulin resistance is discussed, and recommendations for clinical evaluation of affected individuals is provided.

https://bib.irb.hr/datoteka/771355.WJG-20-9330.pdf

Non-alcoholic fatty liver disease and obesity: biochemical, metabolic and clinical presentations.

We present a case of a 36-year-old female patient who was initially admitted to the Department of Infectious Diseases for evaluation of diarrhea. Two years prior to admission, she had been treated in another hospital for erythema nodosum on her calves. There was no further diagnosis at that time. The patient presented with frequent loose stool for three weeks before admission to our Department, at the time without any bloody tinge present. Four days before admittance, the patient’s temperature rose to 39°C, with bloody loose stools and a C-reactive protein (CRP) level of 42.8 mg/L. On the fourth day of hospitalization, laboratory tests showed anemia and erythrocyte sedimentation rate (ESR) of 62 mm/3.6 ks. The next day, the patient developed generalized pyogenous pustules with necrotizing borders on her skin. Serologic testing was negative for VDRL, HIV, ANA, HBsAg, and HCV antibodies, as well as and RA factor. Skin ulcer smear was sterile, and chest X-ray and abdominal ultrasound did not reveal any abnormality. Pathohistological analysis of the skin biopsy specimen was compatible with pyoderma gangrenosum (PG). The dermatologist established a diagnosis of severe generalized PG. Stool samples tested negative for infectious agents. Laboratory tests showed progressed anemia, higher leukocyte levels, ESR of 86 mm/3.6 ks, and CRP level of 151 mg/L. On the fourteenth day of hospitalization, a colonoscopy was performed and showed that the mucosa of the descending colon and rectum was completely covered with ulcerations and pseudopolypous lesions (Figure 1). The patient was transferred to our Department. Pathohistological specimens taken during colonoscopy were confirmed to be positive for ulcerative colitis (UC). Within a few days of the commencement of appropriate treatment, the patient’s general condition improved considerably, stool frequency diminished, her laboratory parameters (ESR, CRP) regressed, and her skin lesions showed significant signs of healing (Figure 2). PG is a sterile inflammatory neutrophilic dermatosis characterized by recurrent cutaneous ulcerations with mucopurulent or hemorrhagic exudate (1). Esti-

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Davorka Lulic

Papers

Non-alcoholic fatty liver disease and obesity: biochemical, metabolic and clinical presentations.

Generalized pyoderma gangrenosum associated with unrecognized ulcerative colitis.