Cytokeratin 18 fragment is associated with steatosis-associated fibrosis estimator score and lipid in patients with steatotic liver disease

The high triglyceride (TG) and low high density lipoprotein (HDL) cholesterol dyslipidemia has been associated with increased postprandial lipemia. Although fasting TG is a powerful predictor of postprandial hyperlipidemia, the role of hypoalphalipoproteinemia in postprandial TG metabolism is uncertain. We have studied postprandial lipemia among 63 men with low fasting plasma HDL cholesterol concentrations (<0.9 mmol/L), but with either low (<2.0 mmol/L) or high (>2.0 mmol/L) fasting plasma TG levels. A significant relationship was noted between postprandial TG response and fasting HDL cholesterol concentration (r = -0.43; P: < 0.0005). We also found that men with high TG/low HDL dyslipidemia (high TG and low HDL cholesterol; n = 16) were characterized by abdominal obesity as well as increased visceral adipose tissue accumulation, whereas normolipidemic controls (low TG and high HDL cholesterol; n = 26) and men with isolated low HDL cholesterol concentrations (low TG and low HDL cholesterol; n = 17) were not characterized by features of the insulin resistance syndrome (visceral obesity, hyperinsulinemia, and hypertriglyceridemia). Although controls and men with isolated low HDL cholesterol levels had similar postprandial lipemic responses, men with the high TG/low HDL dyslipidemia had a marked increase in their postprandial TG responses to the fat load compared with the other subgroups (P: < 0. 001). Men with the high TG/low HDL dyslipidemia were also characterized by higher concentrations of apolipoprotein (apo) B-48 and B-100 particles (chylomicron remnants and very low density lipoproteins, respectively) before and during the postprandial period compared with the other subjects. These results suggest that low HDL cholesterol concentration is a heterogeneous metabolic phenotype that it is not associated with postprandial hyperlipidemia unless accompanied by other features of the insulin resistance syndrome.

We read with interest the article by Feldstein et al. that evaluated the use of cytokeratin-18 (CK-18) fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis (NASH).1 The authors reported that plasma levels of an apoptosis-associated CK-18 fragment were significantly elevated in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) as compared to healthy individuals. Moreover, they observed significantly higher CK-18 fragment levels in NASH compared to "borderline diagnosis" or simple steatosis. The authors conclude that such noninvasive determination of CK-18 fragments allows the prediction of NASH and severity of disease in patients with NAFLD. Liver biopsy is still considered the gold standard for assessment of liver disease activity, although it remains associated with several disadvantages including high costs and risks of clinical complications. Noninvasive techniques that can monitor disease activity and distinguish NASH from simple steatosis are therefore urgently needed.2 The multicenter study by Feldstein and coworkers is therefore of great clinical importance. Caspase-generated CK-18 fragments are released during hepatocyte apoptosis, a fundamental process in virtually all acute and chronic liver diseases that are characterized by inflammation, steatosis, or fibrosis.3-6 Previous studies in patients with chronic HCV infection have shown that activation of hepatic caspases closely correlates with inflammation.7 In addition, detection of caspase-generated CK-18 fragments in sera from patients with chronic hepatitis C virus (HCV) infection has recently been associated with fibrotic liver injury.8 Another study showed a correlation of CK-18 fragment levels with the proportion of HCV-associated liver steatosis.9 In this latter study, only patients with minimal inflammatory disease activity and low stages of fibrosis were included, suggesting that even under conditions of mild inflammation, CK-18 fragment levels correlate with the extent of steatosis. Hepatocyte apoptosis and elevated CK-18 fragment levels are also prominent features of cholestatic liver diseases.10 Furthermore, presumably due to increased cell turnover, elevated serum levels of CK-18 fragments have been reported even in noncirrhotic hepatocellular carcinoma.10 In conclusion, CK-18 fragments represent a strong predictor and useful noninvasive biomarker for the diagnosis of NASH in well-defined patients. However, it should be taken into account that a variety of hepatic pathologies may result in elevated CK-18 fragment levels. Thus, this marker is not specific for NASH but rather a general indicator of severe liver disease. Heike Bantel*, Matthias J. Bahr*, Klaus Schulze-Osthoff , * Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany, Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.

Early highly active antiretroviral therapy (HAART) is recommended for HIV-1-infected infants. There are limited data on lipid changes during infant HAART. Nonfasting total (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol and triglycerides (TG) were measured at 0, 6 and 12 months. Correlates of lipid levels and changes post-HAART were assessed using linear regression. Among 115 infants, pre-HAART median age was 3.8 months, CD4% was 19% and weight-for-age Z score was -2.42. Pre-HAART median lipid levels were: TC, 108.7 mg/dL; LDL, 42.5 mg/dL; HDL, 29.4 mg/dL and TG, 186.9 mg/dL. Few infants had abnormally high TC (6.2%) or LDL (5.6%), but many had low HDL (76.5%) or high TG (69.6%). Higher pre-HAART weight-for-age and height-for-age Z scores were each associated with higher pre-HAART TC (P = 0.04 and P = 0.01) and LDL (P = 0.02 and P = 0.008). From 0 to 6 months post-HAART, TC (P < 0.0001), LDL (P < 0.0001) and HDL (P < 0.0001) increased significantly, and 23.1% (P = 0.002), 14.0% (P = 0.2), 31.3% (P < 0.0001) and 50.8% (P = 0.2) of infants had abnormally high TC, high LDL, low HDL and high TG, respectively. Changes in TC and HDL were each associated with higher gain in weight-for-age Z score (P = 0.03 and P = 0.01) and height-for-age Z score (P = 0.01 and P = 0.007). Increased change in LDL was associated with higher gain in height-for-age Z score (P = 0.03). Infants on protease inhibitor-HAART had smaller HDL increase (P = 0.004). Infants had substantive increases in lipids, which correlated with growth. Increases in HDL were attenuated by protease inhibitor-HAART. It is important to determine clinical implications of these changes.

High density lipoprotein (HDL) levels have been shown to be inversely correlated with the incidence of coronary artery disease (CAD). Since we have previously found that peripheral blood mononuclear cells (PBMC) from persons with high (n = 10) or low HDL (n = 10) have different functional properties, we wanted to examine the PBMC membrane lipid composition and fluidity, as well as to characterize the serum lipoproteins in greater detail. In persons with high HDL, PBMC membrane phospholipids were higher, and the cholesterol/phospholipid (CH/PL) ratio lower than in persons with low HDL. Membrane cholesterol and phospholipids were positively correlated with serum HDL2. The fatty acid composition of membrane phospholipids, and membrane fluidity was similar. The median saturated/unsaturated fatty acid (SFA/UFA) ratio tended to be lower in PBMC membranes and in serum from persons with high HDL; however this was not statistically significant. In serum, total phospholipids and HDL2 components (cholesterol, phospholipids and protein) were higher in persons with high HDL, whereas non-esterified fatty acids (NEFA) and very low density lipoprotein (VLDL) components (triglycerides, cholesterol, phospholipids and protein) were lower. Furthermore, serum cholesterol esters and the cholesterol esters/free cholesterol (CE/FC) ratio was higher, and the atherogenic index, i.e. (apoB X (total cholesterol-HDLc)/apoA-I X HDLc, lower in persons with high HDL. These results demonstrate that PBMC from persons with high or low serum HDL have a different lipid composition presumably of importance for cell function, lipid transport and atherogenesis.

High density lipoprotein (HDL) cholesterol concentrations have been shown to increase with regular endurance exercise and, therefore, can contribute to a lower risk of coronary heart disease in physically active individuals compared with sedentary subjects. Although low HDL cholesterol levels are frequently observed in combination with hypertriglyceridemia, some individuals may be characterized by isolated hypoalphalipoproteinemia, ie, low HDL cholesterol levels in the absence of elevated triglyceride (TG) concentrations. The present study compared the responses of numerous lipoprotein-lipid variables to a 20-week endurance exercise training program in men categorized on the basis of baseline TG and HDL cholesterol concentrations: (1) low TG and high HDL cholesterol (normolipidemia), (2) low TG and low HDL cholesterol (isolated low HDL cholesterol), (3) high TG and high HDL cholesterol (isolated high TGs), and (4) high TGs and low HDL cholesterol (high TG/low HDL cholesterol). A series of physical and metabolic variables was measured before and after the training program in a sample of 200 men enrolled in the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study. At baseline, men with high TG/low HDL cholesterol had more visceral adipose tissue than did men with isolated low HDL cholesterol and men with normolipidemia. The 0.4% (not significant) exercise-induced increase in HDL cholesterol levels in men with isolated low HDL cholesterol suggests that they did not benefit from the "HDL-raising" effect of exercise. In contrast, men with high TG/low HDL cholesterol showed a significant increase in HDL cholesterol levels (4.9%, P<0.005). Whereas both subgroups of men with elevated TG levels showed reductions in plasma TGs ( approximately -15.0%, P<0.005), only those with high TG/low HDL cholesterol showed significantly reduced apolipoprotein B levels at the end of the study (-6.0%, P<0.005). Multiple regression analyses revealed that the exercise-induced change in abdominal subcutaneous adipose tissue (10.6%, P<0.01) was the only significant correlate of the increase in plasma HDL cholesterol with training in men with high TG/low HDL cholesterol. Results of the present study suggest that regular endurance exercise training may be particularly helpful in men with low HDL cholesterol, elevated TGs, and abdominal obesity.

To determine the relative contributions of triglycerides (TGs) and high-density lipoprotein (HDL) cholesterol in the residual risk of coronary heart disease (CHD) after the reduction of low-density lipoprotein (LDL) cholesterol to guideline-recommended levels, we conducted a hospital-based, case-control study with optimal matching in the strata of LDL cholesterol, gender, ethnicity, and age. The 170 cases and 175 controls were patients at Brigham and Women's Hospital (Boston, Massachusetts) from 2005 to 2008 who had an LDL cholesterol level <130 mg/dl. The cases had incident CHD, and the controls had diagnoses unrelated to CHD. The 170 cases and 175 controls had a mean LDL cholesterol level of 73 and 87 mg/dl, respectively. The association between TG and HDL cholesterol levels and CHD risk was assessed using conditional and unconditional logistic regression analysis. The models investigated accommodated the possibility of an interaction between lipid factors. The odds of CHD increased by approximately 20% per 23-mg/dl increase in TGs and decreased by approximately 40% per 7.5-mg/dl decrease in HDL cholesterol. High TGs and low HDL cholesterol interacted synergistically to increase the odds ratio to 10 for the combined greatest TG (> or =190 mg/dl) and lowest HDL cholesterol quintiles (<30 mg/dl). High TG levels were more strongly associated with CHD when the HDL cholesterol was low than average or high; and low HDL cholesterol levels were more strongly associated with CHD when the TGs were high. TGs and HDL cholesterol were associated with CHD in patients with a LDL cholesterol level of < or =70 mg/dl, with a risk similar to, or greater than, those in the total group. In conclusion, high TG and low HDL cholesterol levels contribute strongly and synergistically to CHD when LDL cholesterol is well controlled. Thus, high TGs might have greater importance in patients with optimal rather than greater LDL cholesterol concentrations.

Background/Introduction Low levels of high-density lipoprotein (HDL) have been associated with adverse cardiovascular events in multiple epidemiological studies. Evidence regarding the role of HDL in males and females with established coronary artery disease undergoing percutaneous coronary intervention (PCI) with drug eluting stents (DES) is scarce. Purpose We sought to investigate the impact of low HDL levels on 1-year cardiovascular outcomes in males and females undergoing PCI with DES. Methods We screened all patients undergoing PCI in our center from 2012 to 2017. Exclusion criteria were: unavailable baseline HDL measurement, age &amp;lt;18 years, presentation with ST-segment elevation myocardial infarction (MI) or shock, coexisting neoplastic disease and treatment without a stent or with a bare metal stent. The final population was divided by gender and further stratified to the high or low HDL group according to baseline HDL levels. Cut-offs were 40mg/dL in males and 50mg/dL in females, per the most recent ACC/AHA guideline recommendations. The primary endpoint of the analysis was major adverse cardiovascular events (MACE) at 1 year, defined as death, MI or target vessel revascularization (TVR). To account for potential clinical and anatomical confounders the outcomes were also adjusted for age, Caucasian ethnicity, hypertension, diabetes mellitus (DM), body mass index, smoking, prior MI, multi-vessel disease and type B2/C lesions. Results Out of the 10,843 patients included, 7,718 (71.2%) were male and 3,125 (28.8%) were female. Low HDL was noted in 58.5% of males and 63.8% of females. Patients with low HDL were younger and had a higher prevalence of DM, prior MI, smoking and multi-vessel disease. When comparing low to high HDL groups in terms of 1-year MACE a borderline significant difference was shown in males (7.4% vs. 6.0%; p-value=0.08) but not in females (7.7% vs 8.1%; p-value=0.90) [Panel A]. The numerically higher incidence of MACE in males with low HDL was primarily driven by TVR (5.4% vs 3.7%; p-value=0.005) while the rates of Death (1.4% vs. 1.3%; p=0.96) and MI (2.0% vs. 1.8%; p-value=0.89) were similar between the two groups. After adjustment the male low HDL subgroup remained at a higher risk for 1-year TVR but not 1-year MACE compared to the male high HDL subgroup [Panel B]. No difference for any individual component of MACE was shown between low and high HDL subgroups in females [Panel C]. Conclusion(s) High HDL levels were associated with a lower incidence of TVR and borderline reduction of MACE in male but not female patients undergoing PCI with DES. No difference was demonstrated in terms of death or MI between the high and low HDL subgroups at 1-year follow-up. Impact of HDL levels according to gender Funding Acknowledgement Type of funding source: None

Low serum levels of high-density lipoprotein (HDL) are commonly encountered in patients with coronary artery disease (CAD). An example of this type of patient is a 42-year-old white man with a history of sudden-onset angina secondary to a 90% obstructive lesion along the proximal left anterior descending coronary artery. The family history was significant for his father, who died of a myocardial infarction (MI) at age 44 years. The patient underwent percutaneous transluminal angioplasty with stenting but developed in-stent restenosis. He underwent cutting balloon angioplasty and brachytherapy and was asymptomatic for approximately 6 months. The stent then developed a high-grade occlusion with recurrence of angina, and the patient required single-vessel bypass surgery. The patient’s baseline serum lipid profile revealed low-density lipoprotein (LDL) 128 mg/dL, HDL 27 mg/dL, and triglycerides 92 mg/dL. His lipoprotein(a), C-reactive protein, and homocysteine levels were normal. He was not hypertensive, had no impairment of glycemic control, and did not smoke. With a combination of simvastatin 40 mg and niacin (Niaspan; Kos Pharmaceuticals) 1000 mg daily, the patient’s lipid profile improved, with LDL 78 mg/dL, HDL 43 mg/dL, and triglycerides 60 mg/dL. Follow-up stress testing demonstrated normal myocardial perfusion, and the patient has been asymptomatic for 2 years. With few exceptions, low HDL is an independent risk factor for CAD in case-control and prospective observational studies. In contrast, high HDL levels are associated with longevity and are protective against the development of atherosclerotic disease. In the Framingham Study, risk for CAD increases sharply as HDL levels fall progressively below 40 mg/dL.1 In the Quebec Cardiovascular Study, for every 10% reduction in HDL, risk for CAD increased 13%.2 Many clinicians believe that low HDL is associated with increased CAD risk because it is a marker for hypertriglyceridemia and elevated remnant particle concentrations. The Prospective Cardiovascular Munster …

Obesity and Atherogenic Dyslipidemia

Background: Animal studies suggest in utero exposures to endocrine disrupting chemicals (EDCs) have differential effects by sex on adolescent fat mass and risk of metabolic syndrome, but few human studies account for effects of EDC exposures during the pubertal transition. Aim: Examine the impact of in utero and peripubertal exposures to lead, BPA and phthalates on measures of metabolic syndrome risk at ages 8-13 in a well-characterized Mexico City birth cohort. Methods: Among 118 males and 130 females, mean age 10.3 (SD 1.7) years, we modeled the association of log-transformed maternal bone lead at 1 month postpartum, peripubertal blood lead and phthalates and bisphenol A (BPA) from maternal 3rd trimester and peripubertal urines adjusted for specific gravity on: fasting leptin, glucose, high density lipoproteins (HDL), and triglycerides (TG), adjusting for sex, age, maternal education, socioeconomic status, and birth cohort. Results: In utero lead exposure (mg/g tibia bone) was associated with higher HDL (0.75 mg/dL, p=.0005) in males, but concurrent blood lead with lower HDL (-3.7, p=.06) in females. Adolescent BPA (ng/ml) was marginally associated with higher log levels of leptin (0.21, p=.07) in males and with glucose (8.83 mg/dL, p=.10) in a subsample of both sexes (n=32). Phthalates were negatively related to adolescent log leptin levels in males (3rd trimester MIBP: -0.24, p=.05) and females (3rd trimester MBzP: -0.17, p=.03; concurrent MBP: -0.19, p=.03). In the subsample (n=32), most 3rd trimester phthalates were significantly associated with 5-8 mg/dL lower adolescent HDL levels; concurrent MEP was associated with higher glucose (4.0 mg/dL, p=.05) and MEHHP and MEOHP with higher TG (p&lt;.08). Conclusions: Representative EDC exposures to lead, BPA and phthalates in utero and peripuberty were differentially related by sex to measures of metabolic syndrome risk, particularly HDL, and the magnitude of effect estimates varied by EDC and timing of exposure.

In severe trauma, sepsis or during surgery, bacterial lipopolysaccharide (LPS) frequently enters the circulation. Persons with high levels of high-density lipoprotein (HDL) have previously demonstrated higher monocyte procoagulant activity (PCA) when whole blood is challenged with LPS. The aim of the study was to investigate the distribution of radiolabelled LPS (125I-LPS) in plasma from six persons with high (2.14-2.82 mmol l-1) and six persons with low (0.54-1.04 nmol l-1) HDL, subjecting plasma to fast protein liquid chromatography (FPLC), or agarose electrophoresis followed by quantitative autoradiography. In heparin plasma 125I-LPS was located mainly in parts of plasma containing low-density lipoprotein (LDL) or very low-density lipoprotein (VLDL) and the immunoglobulins, and located to a lesser extent in HDL. However, persons with high HDL showed significantly higher binding of 125I-LPS to HDL and the immunoglobulins, probably to IgG, and significantly lower binding to LDL/VLDL. In calcium-depleted plasma (EDTA) 125I-LPS demonstrated a sharp increase in the binding to HDL, combined with a persistently high binding to LDL/VLDL and binding to the immunoglobulins was almost eliminated in all subjects investigated. Likewise, the binding of 125I-LPS to HDL in EDTA plasma was also significantly higher and to LDL/VLDL significantly lower in persons with high HDL. This study demonstrates that the distribution of 125I-LPS in heparin and EDTA plasma from persons with high or low HDL is different, which is presumed to be of importance concerning the various bioactivities of LPS.

Selective PPAR modulators (SPPARs) may fill the need for treatment of the atherogenic dyslipidemia of insulin resistance and type 2 diabetes: Can they reduce the associated cardiac risk?

Background and aim:In chronic hepatitis C and non-alcoholic fatty liver disease, apoptotic caspases are activated in liver, and serum caspase activity has been suggested as a sensitive marker of early...

Prevalence and pattern of dyslipidemia in hyperglycemic patients and its associated factors among Pakistani population

We investigated the regulation of serum high density lipoprotein (HDL) cholesterol metabolism in patients with type II diabetes mellitus by determining the activities of the two lipolytic enzymes that play major roles in the production and degradation of HDL. The activity of lipoprotein lipase (LPL), the enzyme responsible for HDL cholesterol production, and the activity of hepatic triglyceride lipase (HTGL), the enzyme that facilitates the catabolism of HDL, were measured in plasma obtained after iv injection of heparin. Thirty patients were selected to represent a wide range of serum HDL cholesterol concentrations (low, normal, and high HDL cholesterol groups). Mean lipoprotein lipase activity was similar in all three groups [122 +/- 10 (SEM) U/mL in the low HDL, 141 +/- 11 U/mL in the normal HDL, and 148 +/- 30 U/mL in the high HDL group]. Mean HTGL activity was markedly decreased in the high HDL group; the mean values were 346 +/- 28 U/mL in the low HDL, 320 +/- 25 U/mL in the normal HDL, and 191 +/- 23 U/mL in the high HDL groups, respectively. Body weight and insulin requirement correlated directly with HTGL activity and inversely with serum HDL cholesterol levels. These findings suggest that in type II diabetes mellitus low serum HDL cholesterol levels may be due to an increased rate of clearance by HTGL.